A.P.. 1991. Omega-3 Fatty Acids in Health and Disease and in Growth and Development PDF

Review Article
Omega-3 fatty acids in health and disease

and in growth and development4
Arternis P Simopoulos
ABSTRACT Several sources of information suggest that development. Canada is the first country to provide separate
man evolved on a diet with a ratio ofw6 to w3 fatty acids of 1 dietary recommendations for w6 and w3 fatty acids. Am J
whereas today this ratio is 10:1 to 20-25:1, indicating that Clin Nutr 199 1:54:438-63.
Western diets are deficient in w3 fatty acids compared with the
diet on which humans evolved and their genetic patterns were KEY WORDS Polyunsaturated fatty acids, w3 fatty acids,
established. Omega-3 fatty acids increase bleeding time; decrease w6 fatty acids, lipids, ct-linolenic acid, eicosapentaenoic acid,
platelet aggregation, blood viscosity, and fibnnogen: and increase docosahexaenoic acid, essentiality in growth and development,
cardiovascular disease, hypertension, inflammation, arthritis and
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erythrocyte deformability, thus decreasing the tendency to
thrombus formation. In no clinical trial, including coronary ar- other autoim m une disorders, psoriasis, cancer, prostaglandins,
tery graft surgery, has there been any evidence of increased blood leukotrienes, interleukins, platelet-derived growth factor, en-
loss due to ingestion of w3 fatty acids. Many studies show that dothelium-derived relaxing factor
the effects of w3 fatty acids on serum lipids depend on the type
Contents
of patient and whether the amount of saturated fatty acids in
the diet is held constant. In patients with hyperlipidemia, w3 Introduction 439
fatty acids decrease low-density-lipoprotein (LDL) cholesterol Omega-3 and w6 fatty acids: sources, elongation,
if the saturated fatty acid content is decreased, otherwise there and desaturation 441
is a slight increase, but at high doses (32 g) they lower LDL Evolutionary aspects: the w3 and u6 fatty acid balance 441
cholesterol: furthermore, they consistently lower serum triglyc- Large-scale production of vegetable oils 442
erides in normal subjects and in patients with hypertriglycer- Agribusiness and modern agriculture 443
idemia whereas the effect on high-density lipoprotein (HDL) Imbalance of w6:3 443
varies from no effect to slight increases. The discrepancies be- Biological effects ofw3 fatty acids in relation to coronary
tween animal and human studies most likely are due to differ- heart disease and hypertension 444
ences between animal and human metabolism. In clinical trials Eicosanoid metabolism 444
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) Molecular aspects and gene expression:
in the form of fish oils along with antirheumatic drugs improve beyond the eicosanoids 444
joint pain in patients with rheumatoid arthritis: have a beneficial Hypolipidemic effects 445
effect in patients with ulcerative colitis: and in combination with Effects on normal subjects 445
drugs, improve the skin lesions, lower the hyperlipidemia from Effects on patients 445
etretinates, and decrease the toxicity of cyclosporin in patients Antiatheromatous actions 446
with psoriasis. In various animal models w3 fatty acids decrease Antithrombotic effects 447
the number and size of tumors and increase the time elapsed Vascular effects 447
before appearance oftumors. Studies with nonhuman primates Antiarrhythmic effects 447
and human newborns indicate that DNA is essential for the Effects on restenosis 447
normal functional development of the retina and brain, partic- Effects on lipoprotein (a) 448
ularly in premature infants. Because w3 fatty acids are essential Additional effects 448
in growth and development throughout the life cycle, they should
be included in the diets of all humans. Omega-3 and w6 fatty I From the Center for Genetics, Nutrition and Health, Washington,
acids are not interconvertible in the human body and are im- DC.
2 Supported in part by The Council for Responsible Nutrition (CRN),
portant components ofpractically all cell membranes. Whereas
cellular proteins are genetically determined, the polyunsaturated Washington, DC.
3 This review paper was prepared at the request of CRN and was
fatty acid (PUFA) composition ofcell membranes is to a great
submitted to the Food and Drug Administration by the CRN on De-
extent dependent on the dietary intake. Therefore appropriate
cember 19. 1990.
amounts ofdietary w6 and w3 fatty acids need to be considered 4 Address reprint requests to AP Simopoulos, The Center for Genetics,
in making dietary recommendations, and these two classes of Nutrition and Health. 2001 S Street. NW, Suite 530, Washington, DC
PUFAs should be distinguished because they are metabolically 20009.
and functionally distinct and have opposing physiological func- Received February 27, 1991.
tions. Their balance is important for homeostasis and normal Accepted for publication March 20, 1991.
438 Am J C/in Nutr 1991:54:438-63. Printed in USA. © 1991 American Society for Clinical Nutrition
w3 FATTY ACIDS IN HEALTH AND DISEASE 439
Coronary heart disease 449 olism and decrease triglycerides; and in high doses w3 fatty acids
Hypertension 450 lower cholesterol and have antithrombotic and anti-inflamma-
Inflammatory and autoimmune disorders 451 tory properties. These studies were extensively reviewed and re-
Arthritis 451 ported (23-28).
Psoriasis 451 The 1980s were a period ofexpansion in our knowledge about
Ulcerative colitis 452 polyunsaturated fatty acids (PUFAs) in general and w3 fatty
Cancer 452 acids in particular. Today we know that w3 fatty acids are es-
Diabetes 452 sential for normal growth and development and may play an
Omega-3 fatty acids as an adjuvant to drug therapy 453 important role in the prevention and treatment ofcoronary artery
Essentiality: the role of w3 fatty acids in growth disease, hypertension, arthritis, other inflammatory and au-
and development 453 toimmune disorders, and cancer. Research has been carried out
Animal studies 453 in animal models, tissue cultures. and humans. The original
Human studies 453 observational studies have given way to controlled clinical trials.
Pregnancy 453 A new arena for w3 fatty acids has emerged as adjuvants to drug
Fetal development, human milk, and infant feeding 453 treatment leading to synergism (potentiating the effects of drugs)
Children, adults, and elderly adults 455 or to decreasing their toxicity. This immense expansion in our
Dietary implications 455 knowledge is shown by the increase in the number of publications
Conclusions 457 from 1 10 in 1984 to 319 in 1989 worldwide (based on January
Addendum 458 10, 1990, NIH-MEDLINE search output), amounting to 1541
References 458 for the 5-year period (Fig I) (29). In September 1 989 the US
National Library ofMedicine published a selective bibliography

on the health benefits offish oils that included publications from
Introduction
January 1985 to May 1989 but was intentionally limited to hu-
In the 1950s many investigators studied the effects ofcorn oil man studies. Cited were 576 articles published in 1 55 journals
and fish oil in humans primarily by determining their effects on from around the world. The bibliography is indicative of the
serum cholesterol concentrations in patients with atherosclerosis explosive and expanding interest in the health benefits of fish
(1-5). Corn oil (w6 fatty acid), an odorless, clear oil, was found oils and w3 fatty acids.
to lower cholesterol, particularly when it replaced butter or lard Although a number of important conferences had been held
in the diet. Although sardine oil (w3 fatty acid) had similar effects before 1985, such as the Reading conference held in 1984, the
and in addition lowered serum triglyceride concentrations, it expansion ofthis impressive growth in our knowledge can almost
was not given the attention it deserved (2). Vegetable oils rich be dated from the 1985 conference Health Effects of Polyun-
in w6 fatty acids displaced other fats in the US diet and eventually saturated Fatty Acids in Seafoods, held June 24-25, 1985, in
in the diet of Western Europeans, on the evidence of their hy- Washington, DC (24). The 1985 conference was the first major
pocholesterolemic properties. Omega-3 fatty acids were not international conference to establish the fact that w3 fatty acids
considered as important agents in the control of cardiovascular of marine origin, EPA and docosahexaenoic acid (DHA), play
disease (CVD) despite experimental and clinical work pointing important roles in prostaglandin metabolism, thrombosis and
to their importance (6-9). With the emphasis on the lipid hy- atherosclerosis, immunology and inflammation, and membrane
pothesis, the lowering ofserum cholesterol became the dominant function. The 1985 conference participants recommended 1)
factor for the control of coronary heart disease (CHD). As a the support of research on the role of w3 fatty acids in growth
result the primary contributions ofinflammation and thrombosis and development and in health and disease and on the mech-
in the development of CHD were not adequately investigated anisms involved and 2) the establishment of a test-materials
until the late l970s and l980s and now. program to specifically define nutritional requirements through-
In the 1970s Bang and Dyerberg ( 10- 1 2) reported their find- out the life cycle, and dose and type of w3 fatty acid in inter-
ings that Eskimos had low rates ofCHD and cancer despite their vention studies and in clinical trials.
high-fat diet. Bang and Dyerberg (1 3, 14) emphasized the im- After the conference the National Institutes of Health (NIH)
portance of eicosapentaenoic acid (EPA) in the prevention of published a series of program announcements inviting appli-
heart attacks because of its antithrombotic effects, the increase cations for research on the role of w3 fatty acids in growth and
in bleeding time, and its effect in lowering serum cholesterol development and in health and disease (Table 1)(29). To support
concentrations. Subsequently other epidemiologic studies con- the research, in December 1986 the US Department of Corn-
firmed these findings and showed that fish-eating populations merce developed a special program, the Biomedical Test Ma-
other than the Eskimos had less CVD than did those who con- terials (BTM) program, which provides standardized test ma-
sumed less fish ( 1 5-20). Even as little as 30-40 g of fish twice a terials of known composition of EPA and DHA nationally and
week made a difference (1 7). In two other studies this effect of internationally. These test materials contain 0.2 mg tertiary bu-
higher fish intake was not seen, most likely because of simul- tylhydroquinone (TBHQ)/g as an antioxidant and 2 mg to-
taneous high saturated fatty acid intake (2 1, 22). copherols/g (30).
Additional clinical investigations and experimental studies The response of the scientific community made it obvious
confirmed the initial observations: when diets are supplemented from the very beginning that research with w3 fatty acids would
with o3 fatty acids, the latter partially replace the w6 fatty acids develop along two avenues: 1) studies on the essentiality of the
in the membranes of practically all cells (ie, erythrocytes, plate- w3 fatty acids that would define their role in growth and devel-
lets, endothelial cells, monocytes, lymphocytes, granulocytes, opment throughout the life cycle based on the deficiency model
neuronal cells, fibroblasts, retinal cells, hepatic cells, and neu- and improvement in various functions upon supplementation
roblastoma cells); o3 fatty acids modulate prostaglandin metab- with w3 fatty acids and 2) studies involving mechanisms in the
440 SIMOPOULOS
I
-J
z
w
z
-I
0
w
C
C
C)
.5
U)
C)
.5

z
Year
FIG I . Publications of marine oil and fish oil and w3 fatty acid studies retrieved from MEDLINE (National Library
of Medicine, National Institutes of Health) from 1984 to 1989. (Data as ofianuary 10, 1990, from MEDLINE. By
June 1989 the total number of publications for 1989 was 386.) Reproduced with permission from reference 29.
understanding of chronic diseases that would use the supple- medical and nutrition journals (27, 28, 35-37). The most recent
mentation approach by increasing the amount offish in the diet, research advances were extensively discussed at the Second In-
substituting fish for meat, or using fish oils. ternational Conference on the Health Effects ofOmega-3 Poly-
Since 1985 many conferences have been held in various parts unsaturated Fatty Acids in Seafoods, held March 20-23, 1990,
of the world to review progress in the field, define gaps in the in Washington, DC (25).
knowledge, and develop a research agenda (24, 25, 3 1-34). In This paper presents the state ofthe art in w3 fatty acid research,
addition, major reviews and commentaries appeared in leading drawn from the published literature, the NIH database Computer
TABLE I
Requests for applications (RFAs) and program announcements (PAs) by NIH and ADAMHA: December 6, 1985, to April 17, l987
Date Title Type Institute
December 6. 1985 Biological Mechanisms ofw3 Fatty Acids in Health and PA NCC. (NIADDK, NINCDS. NIAID NICHD,
Disease States NIGMS, NEI, NIEHS, NIA, NIAAA,
NIMH)
June 1986 Studies ofw3 Polyunsaturated Fatty Acids in RFA NHLBI
Thrombosis and Cardiovascular Disease
August 22. 1986 The Role ofw3 Polyunsaturated Fatty Acids in Cancer PA NCI
Prevention
April 17, 1987 The Role ofw3 Polyunsaturated Fatty Acid in Cancer PA NCI
Prevention (reissued)
October 22, 1987 Fatty Acid Derived Mediators of Inflammation RFA NIAID
S Reproduced with permission from reference 29.

NIH: National Institutes of Health: ADAMHA: Alcohol, Drug Abuse and Mental Health Administration: NCC: Nutrition Coordinating Committee:
NIADDK: National Institute of Diabetes and Digestive and Kidney Diseases: NINCDS: National Institute of Neurological and Communicative
Disorders and Stroke: NIAID: National Institute of Allergy and Infectious Diseases: NICHD: National Institute of Child Health and Human De-
velopment: NIGMS: National Institute of General Medical Sciences: NEI: National Eye Institute: NIEHS: National Institute of Environmental
Health Sciences: NIA: National Institute on Aging: NIAAA: National Institute on Alcohol Abuse and Alcoholism: NIMH: National Institute of
Mental Health: NHLBI: National Heart, Lung, and Blood Institute: NCI: National Cancer Institute: and NIAID: National Institute ofAllergy and
Infectious Diseases.
Omega Carbons hand is found in the chloroplast ofgreen leafy vegetables. Both
EFAs are metabolized to longer-chain fatty acids of 20 and 22
a-tlnolenlc H, ““‘‘R.COOH
carbon atoms. LA is metabolized to arachidonic acid (AA) and
LNA, to EPA and DHA, increasing the chain length and degree
of unsaturation by adding extra double bonds to the carboxyl
Unolslc H3 group (Fig 3).
Humans and animals except for carnivores such as lions and
cats can convert LA to AA and LNA to EPA and DHA (38).
This conversion was shown by using deuterated LNA (39). There
is competition between w3 and w6 fatty acids for the desaturation
coO) H,C R.COOH
enzymes. However, both -4 and -6 desaturases prefer w3 to
FIG 2. Structural formulas for w3 (a-linoleic), ,6 (linoleic), and w9 w6 fatty acids (38, 40, 4 1). There is some evidence that -6
(oleic) fatty acids. The first number (before the colon) gives the number desaturase decreases with age (38). Premature infants (42), hy-
of carbon atoms in the molecule and the second gives the number of pertensive individuals (43), and some diabetics (44) are limited
double bonds. w3, w6, and w9 indicate position ofthe first double bond in their ability to make EPA and DHA from LNA. These findings
in a given fatty acid molecule. are important and need to be considered when making dietary
recommendations. EPA and DHA are found in the oils of fish,
particularly fatty fish (Table 2) (24). AA is found predominantly
Retrieval of Information on Scientific Projects (CRISP), and in the phospholipids of grain-fed animals.
presentations at the 1990 conference. LA, LNA, and their long-chain derivatives are important
components ofanimal and plant cell membranes. In mammals

and birds the w3 fatty acids are distributed selectively among
Omega-3 and w6 fatty acids: sources, elongation, lipid classes. LNA is found in triglycerides, in cholesteryl esters,
and desaturation and in very small amounts in phospholipids. EPA is found in
cholesteryl esters, triglycerides, and phospholipids. DHA is found
Unsaturated fatty acids consist ofmonounsaturates and poly-
mostly in phospholipids. In mammals, including humans, the
unsaturates. There are two classes of PUFAs, w3 and w6. The
cerebral cortex (45), retina (46), and testis and sperm (47) are
distinction between w3 and w6 fatty acids is based on the location
particularly rich in DHA. DHA is one of the most abundant
of the first double bond, counting from the methyl end of the
components ofthe brain’s structural lipids. DHA, like EPA, can
fatty acid molecule. Monounsaturates are represented by oleic
be derived only from direct ingestion or by synthesis from dietary
acid, which can be synthesized by all mammals including hu-
EPA or LNA.
mans. Its double bond is between the 9th and 10th carbon atoms
(Fig 2).
Omega-3 and w6 fatty acids are also known as essential fatty Evolutionary aspects: the w3 and w6 fatty acid balance
acids (EFAs) because humans, like all mammals, cannot make
them and must obtain them in their diet. Omega-6 fatty acids On the basis ofestimates from studies in paleolithic nutrition
are represented by linoleic acid (LA) and w3 fatty acids by and modern-day hunter-gatherer populations, humans evolved
a-linolenic acid (LNA). on a diet that was much lower in saturated fatty acids than is
LA is plentiful in nature and is found in the seeds of most today’s diet. Furthermore, the diet contained small but roughly
plants except for coconut, cocoa, and palm. LNA on the other equal amounts ofw6 and w3 PUFAs (Fig 4) (48-50).
Linoleate series Linolenat.e series
C18:2w6 Linoleic acid C18:3w3 Alpha-Iinolenic acid

6 desaturase 6 desaturase
4 1
C18:3w6 Gamma-linolenic acid C18:4w3
4 1
C20:3w6 Dihomo-gamma-Linolenic Acid C20:4w3
& desaturase & desatwase
4
C20:4w6 Arachidonic acid C20:5w3 Eicosapentaenoic acid
4
C22:4w6 C22:5w3 Docosapentaenoic acid
desaturase
4 4
C22:5w6 Docosapentaenoic acid C22:6w3 Docosahexaenoic acid
FIG 3. Essential fatty acid metabolism desaturation and elongation of w6 and w3.
442 SIMOPOULOS
TABLE 2
Content of w3 fatty acids and other fat components in selected fish
Fatty acids
Total Total Total Total

Fish fat saturated monounsaturated polyunsaturated 18:3 20:5 22:6 Cholesterol
g/iOOg mg/lOOg
Anchovy,
European 4.8 1.3 1.2 1.6 - 0.5 0.9 -
Bass, striped 2.3 0.5 0.7 0.8 Tr 0.2 0.6 80

Bluefish 6.5 1.4 2.9 1.6 - 0.4 0.8 59
Carp 5.6 1.1 2.3 1.4 0.3 0.2 0.1 67
Catfish, brown
bullhead 2.7 0.6 1.0 0.8 0.1 0.2 0.2 75
Catfish, channel 4.3 1.0 1.6 1.0 Tr 0.1 0.2 58
Cod, Atlantic 0.7 0. 1 0. 1 0.3 Tr 0. 1 0.2 43
Croaker, Atlantic 3.2 1.1 1.2 0.5 Tr 0.1 0.1 61
flounder,
unspecified 1.0 0.2 0.3 0.3 Tr 0.1 0.1 46
Grouper, red 0.8 0.2 0.1 0.2 - Tr 0.2 -
Haddock 0.7 0. 1 0. 1 0.2 Tr 0. 1 0. 1 63

Halibut,
Greenland 13.8 2.4 8.4 1.4 Tr 0.5 0.4 46
Halibut, Pacific 2.3 0.3 0.8 0.7 0. 1 0. 1 0.3 32
Herring, Pacific 13.9 3.3 6.9 2.4 0.1 1.0 0.7 77
Herring, round 4.4 1.3 0.8 1.5 0.1 0.4 0.8 28
Mackerel,king 13.0 2.5 5.9 3.2 - 1.0 1.2 53
Mullet,striped 3.7 1.2 1.1 1.1 0.1 0.3 0.2 49
Ocean perch 1.6 0.3 0.6 0.5 Tr 0.1 0.1 42
Plaice, European 1.5 0.3 0.5 0.4 Tr 0.1 0.1 70
Pollock 1.0 0. 1 0. 1 0.5 - 0. 1 0.4 71
Pompano,
florida 9.5 3.5 2.6 1.1 - 0.2 0.4 50
Salmon, Chinook 10.4 2.5 4.5 2.1 0.1 0.8 0.6 -
Salmon, pink 3.4 0.6 0.9 1.4 Tr 0.4 0.6 -
Snapper, red 1.2 0.2 0.2 0.4 Tr Tr 0.2 -
Sole, European 1.2 0.3 0.4 0.2 Tr Tr 0. 1 50

Swordfish 2.1 0.6 0.8 0.2 - 0.1 0.1 39
Trout, rainbow 3.4 0.6 1.0 1.2 0. 1 0. 1 0.4 57
Tuna,albacore 4.9 1.2 1.2 1.8 0.2 0.3 1.0 54
Tuna, unspecified 2.5 0.9 0.6 0.5 - 0.1 0.4 -
S Per 100 g edible portion, raw. Dashes denote lack of reliable data for nutrient known to be present; Tr, trace (< 0.05 g/lOO g food). Adapted
from the United States Department ofAgriculture Provisional Table on the Content ofOmega-3 Fatty Acids and Other Fat Components in Seafoods
as presented by Simopoulos et al (24).
Large-scale production of vegetable oils because LNA in soybean oil caused many organoleptic problems.
It was recently documented that the hydrogenation process and
The increased consumption of w6 fatty acids in the last 100
particularly the formation oftrans fatty acids has led to increases
y is due to the development of technology at the turn of the
in serum cholesterol concentrations whereas LA in its regular
century that marked the beginning of the modern vegetable-oil
industry and to modern agriculture with the emphasis on grain state in oil is associated with a reduced serum cholesterol con-
feeds for domestic livestock (grains are rich in w6 fatty acids) centration (52, 53).
(5 1 ). The invention of the continuous screw press, named Ex- As stated in the introduction, since the 1950s, research on
pellet#{174}
by VD Anderson, and the steam-vacuum deodorization the effects of 6 PUFAs in lowering serum cholesterol concen-
process by D Wesson made possible the industrial production trations has dominated the research support on the role of
ofcottonseed oil and other vegetable oils for cooking(5 1). Solvent PUFAs in lipid metabolism. Although a number of investiga-
extraction of oilseeds came into increased use after World War tom contributed extensively, the paper by Ahrens et al in 1954
I and the large-scale production of vegetable oils became more (1) and subsequent work by Keys et al (2) firmly established
efficient and more economic. Subsequently, hydrogenation was the a6 fatty acids as the important fatty acids in the field
applied to oils to solidify them. The partial selective hydrogen- of CVD. The availability of methods for the production of
ation of soybean oil reduced the LNA content of the oil while vegetable oils and their use in lowering serum cholesterol
leaving a high concentration of LA. LNA content was reduced concentration led to an increase in both the fat content of the
o3 FATTY ACIDS IN HEALTH AND DISEASE 443
Hwiler-Gcf hirer Agr/cu/tirc/ /#thistr#j/
4o
30
____._.._._J2t!I±t___._ --
2O
10
0 L I iT-i
(-4x10 y.wt) (10,000 ysort) 1800 1900 2000
TIME (yetars)

FIG 4. Scheme of the relative percentages of different dietary fatty acids (saturated fatty acids and w6 and w3
unsaturated fatty acids) and possible changes subsequent to industrial food processing, involving fattening of animal
husbandry and hydrogenation of fatty acids. Reproduced from reference 48.
diet and the greater increase in vegetable oils rich in w6 fatty ever, rapid dietary changes over short periods of time as have
acids. occurred over the past 100- 150 y is a totally new phenomenon
in human evolution.
Agribusiness and modern agriculture Homo sapiens made his appearance ‘ 40 000 y ago and the
Agribusiness contributed further to the decrease in w3 fatty human genetic constitution has remained relatively unchanged.
acids in animal carcasses. Wild animals and birds who feed on Then, 10 000 y ago, agriculture began to bring changes slowly
wild plants are very lean, with a carcass fat content ofonly 3.9% in food consumption. It is only since the industrial revolution
(54), and contain about five times more PUFAs per gram than that changes in food consumption have occurred rapidly. These
is found in domestic livestock (55, 56). Most importantly, 4% changes are reflected in increased consumption of animal fat
ofthe fat ofwild animals contains EPA. Domestic beef contains and in imbalances in w6:w3. The ratio that was 1 from veg-
very small or undetectable amounts of LNA because cattle are etable and animal sources during the evolutionary period for
fed grains rich in w6 fatty acids and poor in w3 fatty acids (57) humans is now estimated by Hunter (6 1) to be 10-1 1: 1 from
whereas deer that forage on ferns and mosses contain more w3 vegetable sources. From evidence that the per capita consump-
fatty acids (LNA) in their meat. tion of major foods in 1987 was 61.4 kg red meat, 28.6 kg
Modern agriculture with its emphasis on production has de- chicken, and 6.8 kg fish plus the increases in w6 fatty acids from
creased the w3 fatty acid content in many foods: green leafy vegetable oils, the ratio is closer to 20-25: 1 from vegetable and
vegetables, animal meats, eggs, and even fish (58-6 1 ). Foods
from edible wild plants contain a good balance of w6 and w3
fatty acids (Table 3) (58). Modern aquaculture produces fish TABLE 3
that contain less w3 fatty acid than do fish grown naturally in Fatty acid content of plants*
the ocean, rivers, and lakes (Table 4) (60). As can be seen from
Table S comparing the fatty acid composition of egg yolk from Fatty Buttercrunch Red leaf
acid Purslane Spinach lettuce lettuce Mustard
free-ranging chickens and the standard US Department of Agri-
culture (USDA) egg, the former has an w6-w3 ratio (w6:w3) of mg/g wet WI
1.3 whereas the USDA egg has an w6:w3 of 19.4 (59).
14:0 0. 16 0.03 0.0 1 0.03 0.02
Imbalance of w6.w3 16:0 0.81 0.16 0.07 0.10 0.13
18:0 0.20 0.01 0.02 0.01 0.02
Before the l940s cod-liver oil was ingested mainly by children 18:1w9 0.43 0.04 0.03 0.01 0.01
as a source of vitamins A and D with the usual dose being a 18:2w6 0.89 0.14 0.10 0.12 0.12
teaspoon. Once these vitamins were synthesized consumption 18:3w3 4.05 0.89 0.26 0.31 0.48
of cod-liver oil was drastically decreased. Thus an absolute and 20:5w3 0.01 0.00 0.00 0.00 0.00
relative change of 6:w3 in the food supply of Western societies 22:6w3 0.00 0.00 0.001 0.002 0.001
has occurred over the last 100 y (Fig 4) (48). A balance existed Other I .95 0.43 0. 1 1 0. I 2 0.32
between w6 and w3 for millions of years during the long evo- Total 8.50 1.70 0.60 0.702 1.101
lutionary history of the genus Homo, and genetic changes oc-
curred partly in response to these dietary influences (49). How- 5 Reproduced with permission from reference 58.
444 SIMOPOULOS
TABLE 4
Fat content and fatty acid composition of wild and cultured trout, eel, and
Trout (Salmo gairdneri and

Salmo trutta fario) Eel (Angu i/la anguilla) Salmon (S a/mo salar)
Wild Cultured Wild Cultured Wild Cultured

(n=2) (n=9) (n=4) (n=4) (n=2) (n=2)
Fat (g/lOO g) 5 ± 3 6 ± 1 21 ± 6 30 ± 2t 10 ± 0.1 16 ± 0.64

Fatty acids
(g/ 100 g fatty acid)
l8:3w3 3±2 1 ±0.34 2±2 1 ±0.3 1 ±0.1 1 ±0.1
20:5w3 7±0.6 4 ± 14 4±2 3 ±0.6 5 ±0.2 5 ±0.1
22:6w3 15±2 13 ± lt 4±2 6 ±0.4 10 ±2 7 ±0.lt
Other w3 5 ± 0.6 2 ± 0.74 3 ± 1 2 ± 0.2t 3 ± 0.5 4 ± 0.1
l8:2w6 4±3 9 ±24 2±2 5 ±0.34 1 ±0.1 3 ±0.1
Other w611 I ± 0.4 0.6 ± 0.14 2 ± 0.3 0.4 ± 0.14 0.2 ± 0.1 0.5 ± 0.1
Total w3 30 ± 0.2 20 ± 34 14 ± 3 12 ± I 20 ± 2 17 ± 0.2
Total w6 5 ± 3 9 ± 2t 3 ± 1 6 ± 0.34 2 ± 0.1 3 ± 0.14
w3:w6 7±5 2 ±0.64 5±2 2 ±0.3t 11 ±2 6 ±0.lt
5 Reproduced from reference 60. ± SD; n, number of lots; each lot consisted of about six trout or eel or one or two salmon.

tt Significantly different from wild: tP < 0.05, 4P < 0.01.
§ 18:4w3 + 20:3w3 + 22:5w3.
II 20:4w6 + 22:4w6.
animal sources. From per capita quantities of foods available a decrease in leukotriene B4 formation, an inducer of inflam-
for consumption in the US national food supply in 1985, the mation and a powerful inducer of leukocyte chemotaxis and
amount of EPA is reported to be 50 mg capita I d ‘ and
- adherence; 4 ) an increase in thromboxane a weak platelet
A3 ,
the amount of DHA is 80 mg - capita ‘ d ‘. The-two main aggregator and a weak vasoconstrictor; 5) an increase in pros-
sources are fish and poultry (62). tacyclin PG!3 , leading to an overall increase in total prostacyclin
by increasing PGI3 without a decrease in PG!2 . Both P012 and
PG!3 are active vasodilators and inhibitors ofplatelet aggregation;
Biological effects of w3 fatty acids in relation
and 6) an increase in leukotriene B5 a weak
, inducer of inflam-
to CHD and hypertension
mation and a weak chemotactic agent (63, 64).
Eicosanoid metabolism
Molecular aspects and gene expression:
AA and EPA are precursors of metabolic products that consist
beyond the eicosanoids
of 20 carbon atoms and are known collectively as eicosanoids
(prostaglandins, thromboxanes, and leukotrienes) (Fig 5) (63, The phospholipid class and fatty acid composition and cho-
64). The discovery of prostaglandins and subsequently the rec- lesterol content of biomembranes are critical determinants of
ognition that AA is the precursor of the 2-series of prostanoids physical properties of membranes and have been shown to in-
(prostaglandins and thromboxanes) and of leukotrienes of the fluence a wide variety of membrane-dependent functions, such
4-series expanded the horizons of research on w6 and w3 fatty as integral enzyme activity, membrane transport, and receptor
acids because LA, the precursor ofAA, is the predominant PUFA function. The ability to alter membrane lipid composition and
in the Western diet. EPA and DHA are precursors ofthe pros- function in vivo by diet, even when EFAs are adequately sup-
tanoids of the 3-series and leukotrienes of the 5-series. The dis- plied, demonstrates the importance of diet in growth and me-
covery in 1979, by Needleman et al (65), that prostaglandins tabolism (66).
derived from
EPA have different biological properties than do Complex interactions and displacements of the w3 and w6
those derived from AA stimulated further research on fish oils fatty acids take place in plasma and cellular lipids after dietary
and on the nutritional aspects of prostaglandins. manipulations. Early steps ofcell activation, such as generation
Competition between the two different classes of PUFAs oc- of inositol phosphates, are induced by dietary fatty acids (67).
curs in prostaglandin formation: EPA competes with AA for The effects ofdietary fatty acids on the inositol phosphate path-
prostaglandin and leukotriene synthesis at the cyclooxygenase way indicate that diet-induced modifications of PUFAs at the
and lipoxygenase level. When humans ingest fish or fish oil, the cellular level affect the activity of the enzymes responsible for
EPA and DHA from the diet partially replace the w6 fatty acids, the generation of lipid mediators in addition to the formation
especially AA, in the membranes of probably all cells but es- of products (eicosanoids) directly derived from their fatty acid
pecially in the membranes of platelets, erythrocytes, neutrophils, precursors. This shows that dietary fats affect key processes in
monocytes, and liver cells. As a result, ingestion of EPA and cell function.
DHA from fish or fish oil leads to 1) a decreased production of The role of w3 fatty acids in the control of gene expression is
prostaglandin E2 (POE2) metabolites; 2) a decrease in throm- an area that is expected to expand over the next 5 years as we
boxane A2 , a potent platelet aggregator and vasoconstrictor; 3) begin to understand the role of nutrients in gene expression. It
TABLE 5 lipoprotein (LDL)-cholesterol concentrations > 4. 14 mmol/L
Fatty acid concentrations in chicken egg yolks* and hypertriglyceridemia was defined as plasma triglyceride
concentrations 2.26 mmol/L.
> There were marked variations
Fatty acid Greek egg ______________
Supermarket egg
in the design of the studies. The amount of fish oil varied from
mg/g yolk a low of 1 .6 g/d to > 100 g/d and the w3 fatty acids varied from
0.5 to 25 g/d. The length of intervention varied from 2 wk to
Saturated
> 2 y. The w3 fatty acid intake was in the form of whole fish,
I4:0 1.10 0.70
cod-liver oil, fish-oil concentrate, fatty acid ethyl esters, or pu-
15:0 0.07
I6:0 77.60 56.66 rifled EPA ethyl esters.
I 7:0 0.66 0.34 Effects on normal subjects. Harris (37) found that w3 fatty
I 8:0 21.30 22.88 acids did not influence LDL cholesterol concentration, but a
Total 100.66 80.65 slight rise (‘-3%) occurred in high-density-lipoprotein (HDL)-
Monounsaturated cholesterol concentrations and a 25% decrease occurred in tn-
16:lw7 21.70 4.67 glyceride concentrations. In other well-controlled studies using
I8:1 120.50 109.97 relatively lower doses offish oil (< 20 g/d), similar findings were
20:1w9 0.58 0.68
reported by Sanders and Hochland (70), Zucker et al (7 1), and
22:lw9
Mortensen et al (72). Nagakawa et al (73) used purified EPA
24:1w9 0.04
with no other dietary change. They found modest decreases in
Total 142.78 I15.36
w6
total cholesterol and LDL concentrations, no changes in HDL
l8:2w6 16.00 26.14 concentrations, and a marked decrease in triglyceride concen-
trations.

18:3w6 0.25
20:2w6 0.17 0.36 Effects on patients. In patients with type ha hyperlipidemia,
20:3w6 0.46 0.47 dietary 0)3 fatty acids did not change total or LDL cholesterol,
20:4e6 5.40 5.02 slightly increased HDL, and lowered triglyceride concentrations.
22:4w6 0.70 0.37 In patients with combined hyperlipidemia, type IIb, total cho-
22:56 0.29 1.20
lesterol concentration did not change. LDL and HDL cholesterol
Total 23.02 33.81
concentrations rose by 5-7% and triglyceride concentrations de-
w3
creased by 38%. Similar results were reported in other well-con-
18:3w3 6.90 0.52
20:3w3 0.16 0.03 trolled, low-dose, crossover trials (7 1, 74-76). In patients with
20:5w3 1.20 isolated hypertriglyceridemia, total cholesterol and triglyceride
22:5w3 2.80 0.09 concentrations decreased by 8% and 52%, respectively, and LDL
22:6w3 6.60 I .09 and HDL increased by 30% and 10%, respectively. The decrease
Total 17.66 I.73 in total cholesterol resulted from a fall in very-low-density Ii-
P:St 0.4 0.44 poprotein (VLDL). In patients with type IV hyperlipidemia, LDL
w6:w34 1.3 19.4 cholesterol concentration increased by 20% (75, 77).
These studies suggest that the type of patient studied deter-
S Reproduced with permission from reference 59. Fatty acid com-
mines the hypolipidemic response to w3 fatty acid supplemen-
position and lipid content were determined in hard-boiled eggs.
tation. In patients with hypertriglyceridemia the fall in total cho-
t Ratio of polyunsaturated fatty acids to saturated fatty acids.
lesterol is due to the decrease in VLDL. Sanders (78) in an up-
:1:Ratio of w6 to w3 fatty acids.
dated review reported similar findings. In addition, he found
that in type III patients fish oil lowers triglycerides and choles-
terol. Sanders also reviewed the studies in which w3 fatty acids
is known that nutrients, like hormones, influence and control lowered triglycerides in patients with hypertriglyceridemia and
gene expression, and research is now providing more examples found that these effects of w3 fatty acids are indeed sustained,
(68). Omega-3 fatty acids in the form of menhaden oil lower contrary to reports by Schectman et al (79). Schectman et al
the enzyme fatty acid synthetase in the liver, presumably as a (79) suggested, on the basis ofa study on a small group of patients,
consequence ofa large decrease in fatty acid synthetase mRNA that triglyceride-lowering effects offish oils cannot be sustained.
concentration (69). This suggestion is not supported by other larger controlled trials.
Omega-3 fatty acids have been extensively studied in terms Miller et al (80), in a randomized controlled trial for 3 mo,
of their hypolipidemic, antiatheromatous, anti-inflammatory, showed that the triglyceride-lowering effect of 10 g MaxEPA#{174}/
antithrombotic, vascular, and other effects described below. In d (3.2 g o,3 fatty acids) was sustained. Moreover, Saynor Ct al
fact, more is known about the effects ofw3 fatty acids in human (8 1) showed that the effect is sustained for years. The study of
metabolism than any other class of fatty acids. Schectman et al (79) employed an ester concentrate. The failure
to sustain the triglyceride-lowering effect in that study could well
Hi’polipidemic effects
be related to poor patient compliance (78). Sanders found that
A review ofthe clinical investigations published up to February as little as 6 g fish oil/d (2 g w3 fatty acids) has a triglyceride-
1988 in peer-reviewed English-language journals was earned out lowering effect in hypertriglyceridemic patients. The more com-
by Hams (37) on the effects offish oils on lipids and lipoproteins monly used dose is 3 g/d for EPA and DHA.
in normal volunteers and in patients with primary hyperlipid- In addition to the type of patient, another factor that affects
emia, isolated hypercholesterolemia (type Ila), combined hy- LDL concentration is whether saturated fatty acids are held
perlipidemia (type IIb), and isolated hypertriglyceridemia (types constant or decreased during supplementation. In normal sub-
IV and V). Hypercholesterolemia was defined as low-density- jects when saturated fatty acids were held constant, LDL tended
446 SIMOPOULOS
PLANT METABOLISM MAMMALIAN METABOLISM
Acetyl#{149}CoA
Plastids
Oleic acid
Prostaglandtn G2
Endoplasmic 02
1. retIculum
H3CCOOH vegetable Hf * *S## COOH COO”
LinoIeic acid (w -6) foods Arachidonic acid Cl!3

Chloroplast 024
COOH
a-Linoienic acid (w-3) Len4 )XA
Marine algae Leukotnienes 5
flt(tOfl \44 O24

marine COOl!

H3C,,,,,COoH foods
Eicosapentaenoic acid #{149}CH3
Eicosapentaenoic acid
l Marine algae
7 Plankton
j Fish Prostaglandin G3
I-IC3 cCOOH 7
Docosahexaenoic acid
FIG 5. Origin of w3 and w6 unsaturated fatty acids, biosynthesis of eicosanoids from arachidonic acid (C20:4w6)
and eicosapentaenoic acid (C20:5w3). Reproduced with permission from reference 63.
to rise but when saturated fatty acids were reduced, the LDL glyceride concentrations. Furthermore, Nestel (86) reported that
tended to decrease. In patients with hyperlipidemia in whom fish-oil feeding blunted the expected rise in plasma cholesterol
saturated fatty acids were held constant, LDL increased except concentrations when large amounts of cholesterol were fed to
in the study by Phillipson et al (82), who used a very high dose humans. These findings are consistent with a reduced rate of
offish oil. In general, a high dose offish oil (10 g w3 fatty acids! coronary artery disease in fish-eating populations. Studies in hu-
d) may lower LDL whereas lower doses do not. Whether EPA mans have shown that fish oils reduce the rate ofhepatic secretion
or DHA is more effective in lowering LDL is under investigation of VLDL triglyceride (77, 87-89). In normolipidemic subjects
with more-purified preparations of the individual fatty acids. w3 fatty acids prevent and reverse rapidly the carbohydrate-in-
In summary, the effects ofw3 fatty acids on serum cholesterol duced hypertriglycenidemia (87). There is also evidence from
concentrations are similar to those of other PUFAs. When w3 kinetic studies that fish oils increase the fractional catabolic rate
fatty acids replace saturated fatty acids in the diet, they lower (FCR) ofVLDL (77, 88, 89).
serum cholesterol concentrations. Omega-3 fatty acids have the
added benefit of consistently lowering serum triglyceride con- .4 ntiat/n’ronatoii.s actions
centrations whereas the w6 fatty acids do not and may even The antiatheromatous actions ofw3 fatty acids are supported
increase them (82). by a number ofanimal studies. In dogs fed a diet high in saturated
In considering these aspects ofw3 fatty acids on LDL-choles- fatty acids and cholesterol, supplementation with fish oils pre-
terol concentrations, the issue is whether this increase in LDL vented intimal hyperplasia that is induced on venous allografts
is indeed significant in increasing the risk for atherosclerosis in inserted into their arteries (90). In hyperlipidemic swine model,
patients with type II and IV hyperlipidemia in view of the an- dietary supplementation with cod-liver oil reduced the devel-
tithrombotic, anti-inflammatory, and antivasorestrictive aspects opment of coronary atherosclerosis without any significant
ofw3 fatty acids. Furthermore, the possibility that this new LDL changes in plasma lipid concentrations between the supple-
may not be atherogenic, or as atherogenic, needs to be considered mented animals and the controls (9 1). In the primate model,
because fish-oil diets have produced changes in lipoprotein dietary fat substitution with w3 fatty acids inhibited atherogenesis
composition in animal studies (83-85). Theoretically, EPA and in the aorta, carotid, and femoral arteries (92). Hollander et al
DHA may alter the rate or form of LDL oxidation in vivo and (93) confirmed Davis et al’s (92) findings in another primate
thereby cause a reduced atherogenic potential not reflected in species without significant differences in serum lipid levels. Using
an actual lowering of, or even despite an increase in, LDL con- the rabbit atherogenesis model, Thiery and Seidel (94) found
centration. that fish-oil feeding resulted in an enhancement of cholesterol-
Another important consideration is the finding that during induced atherogenesis whereas Zhu et al (95) found that ath-
chronic fish-oil feeding there is a decrease in postprandial tri- erosclerosis was inhibited by fish oils in cholesterol-fed rabbits.
These conflicting results were observed in the rabbit atherogenesis proliferation of smooth muscle cells, fibroblasts, and macro-
model whereas in all other models (dog, swine, and two primate phages in the arterial wall (105).
species) fish oils were found to have antiatherogenic effects even The endothelium releases an EDRF, presumably nitric oxide.
if they did not lower serum lipids. When animals are fed cod-liver oil or fish oils (EPA plus DHA),
they increase the release of relaxing factors, which facilitates
Antithromhotic effects
relaxation in large arteries and in resistance vessels (106). Also
In addition to a prolongation of bleeding time, there is sub- in the presence of EPA, endothelial cells in culture increase the
stantial agreement that platelet aggregation to epinephrine and release of relaxing factors indicating a direct effect of the fatty
collagen is inhibited, thromboxane A2 production is decreased, acid on the cells. EDRF presumably contributes to antithrom-
whole-blood viscosity is reduced, and erythrocyte membrane botic and antiatherosclerotic effects ofw3 fatty acids by relaxing
fluidity is increased (24, 33, 34, 64, 96). Increased concentrations vascular smooth muscle and inhibiting platelet aggregation.
of plasminogen activator and decreased concentrations of a Increases in PGI2 were shown in tissue fragments from the
plasminogen inhibitor after fish-oil ingestion were reported (97). atrium, aorta, and saphenous vein obtained at surgery in patients
Fibrinogen also decreases after w3 fatty acid ingestion. Although treated with w3 fatty acids (104). This finding is very important
some studies failed to show a decrease in fibrinogen concentra- because it enhances our understanding ofthe effects ofw3 fatty
tions, a randomized, double-blind clinical trial did show a de- acids on vessel walls in humans and differs from the results of
crease after ingestion ofw3 fatty acids in adults with type lIb or
some animal studies (107, 108). Rats do not form PGI3 after
IV hyperlipoproteinemia (98). A decrease in fibrinogen was also
dietary EPA (107, 108) whereas humans do (109). Therefore,
found in another double-blind trial with 64 men aged 35-40 y
the importance of human studies is obvious.
randomly assigned to two groups (99). In the studies that failed
to show an effect, the study by Sanders et al (100) used a small

Antiarrhvthmic effects
dose ofcod-liver oil and the study by Rogers et al (101) included
healthy volunteers and was of short duration. Sudden cardiac death is frequently a consequence of severe
Although a decrease in platelet count occurs with an increase ventricular fibrillation or terminal cardiac arrhythmia. Experi-
in platelet size after ingestion ofw3 fatty acids (especially in very mental studies with isolated papillary muscles from either rats
large quantities), clinical evidence of bleeding has yet to be re- or marmoset monkeys indicate much less susceptibility to cat-
ported. Platelet survival has been found to be normal. Because echolamine-induced arrhythmia in the muscles from animals
there is an increase in platelet size with a decrease in platelet fed fish-oil supplements than from those on w6 or low-fat diets
count, there is no overall decrease in platelet mass (102). When (1 10). Indomethacin abolishes these effects in vitro, suggesting
fish oils are discontinued, the platelet count returns to normal. a mechanism operating via the eicosanoids (prostaglandins). In
In some cases platelet count rebounds to supernormal before studies with adult marmoset monkeys fed dietary fish oil for
returning to normal. The mechanisms ofthese effects offish oil several months, cardiac function improved, and the vulnerability
on platelets and on megakaryocytes are unknown. These effects of the heart to develop cardiac arrhythmia was reduced when
of fish oils leading to an increase in bleeding time has raised subjected to ischemic stress. Burr et al (23) studied the effects
questions: What is the clinical significance of the prolonged ofdietary intervention in the secondary prevention of myocardial
bleeding time? Are there any adverse effects? infarction. A modest intake of fatty fish two-to-three times per
The effects of different doses of fish oils on the prolongation week (or 3 g fish oils/d) reduced all-cause mortality by 29% over
of bleeding time were investigated by Saynor et al (8 1 ). With a 2-y period, possibly by preventing sudden death from an-
1.8 g EPA there was not any prolongation in bleeding time. At rhythmia.
4 g the bleeding time increased and the platelet count decreased
without any adverse effects. In studies in humans there has never Effects on restenosis
been a case of clinical bleeding, even in patients undergoing
angioplasty while they were on fish-oil supplements (103). The antiatheromatous aspects of w3 fatty acids shown in an-
DeCaterina et al (104) recently reported on the preoperative imal experiments suggested the use of w3 fatty acids to prevent
use offish oils in I 3 men and 2 women who underwent coronary- restenosis in patients undergoing angioplasty. The cause of re-
artery-bypass graft surgery. The daily dose was 3 g EPA and 1.3 stenosis is unknown. However platelet aggregation, proliferation
g DHA in purified fish oil that was taken for 28 d before surgery. ofsmooth muscle cells, and coronary vasospasm are considered
The control subjects were 14 men and 1 woman perfectly to be important contributors to restenosis. Although the success
matched for age and severity ofdisease who were scheduled for rate of angioplasty is high, restenosis occurs in 25-40% in the
surgery by the same surgeon. The control subjects did not receive dilated lesions - 6 mo after the procedure. Most studies showed
any fish oils. Despite changes in platelet function, increases in a benefit when co3 fatty acids supplemented the standard regimen
bleeding time, and increases in vascular PG!2. the perioperative before and after surgery (103, 1 1 1, 1 12). Dehmer et al (103)
blood loss was not increased in subjects receiving fish-oil sup- provided evidence that when w3 fatty acids were given to the
plements. There is no evidence that the increase in bleeding patients along with aspirin and dipyridamole 7 d before angio-
time is clinically significant or has any adverse effects. plasty and continued for 6 mo afterward, there was a reduction
in the rate of restenosis on catheterization 3-4 mo after angio-
Vascular effects
plasty. Others report no benefit ( 1 13, 1 14). There was no clinical
It was recently shown that w3 fatty acids inhibit the production evidence of bleeding complications in any treated patient re-
ofplatelet-denived growth factor (PDGF) ( 105) and increase en- ported in these studies. The role ofw3 fatty acids in the preven-
dothelium-derived relaxing factor (EDRF)(l06). Omega-3 fatty tion ofearly restenosis after coronary angioplasty is a major area
acids reduce production of a PDGF-like protein in bovine en- of research because percutaneous transluminal coronary angio-
dothelial cells, which leads to inhibition in the migration and plasty is an important treatment for selected patients with CHD.
448 SIMOPOULOS
TABLE 6 group but were unaffected in the rapeseed-oil group. The total
Effects ofdietary w3 fatty acids on factors and mechanisms involved cholesterol, LDL cholesterol, and apolipoprotein B (apo B) con-
in the development of inflammation, atherosclerosis, and immune
centrations fell significantly in both groups. HDL cholesterol
diseases
increased and triglycerides decreased significantly only in the
Reduce or inhibit risk and/or precipitating factors fish-oil group. Not everybody in the fish-oil group showed a
Arachidonic acid decrease in plasma Lp(a) concentrations. The investigators
therefore subdivided the participants in the study into two groups,
Platelet aggregation
responders and nonresponders. Two-thirds of the people studied
Thromboxane A2 formation
were responders and they showed an average Lp(a) decrease of
Monocyte and/or macrophage function
24%. In this study, tissue plasminogen activator concentrations
Leukotriene formation (LTB4) were reduced significantly in both groups by 16%. There was
Formation of platelet activating factor (PAF) a concomitant but not significant increase of plasma activator
Toxic oxygen metabolites
inhibitor, PAl5.
Interleukin I formation (IL- 1)
In a recent study by Seed et al (1 18) on the relation of serum
Formation of tumor necrosis factor (TNF)
Platelet-derived growth factor-like protein (PDGF)
Lp(a) concentration and apolipoprotein A (apo A) phenotype
to CHD in patients with familial hypercholesterolemia, it was
Intimal hyperplasia shown that “the median lipoprotein(a) level in the 54 patients
Blood pressure and/or blood pressure response with CHD was 57 mg/dl, which is significantly higher than the
corresponding value of 18 mg/dl in the 61 patients without CHD.
Very-low-density and low-density lipoproteins (VLDL, LDL)
According to discriminant-function analysis, the lipopnotein(a)
Triglycerides

level was the best discriminator between the two groups (as
Lipoprotein (a) [Lp(a)]
compared with all other lipid and lipoprotein levels, age, sex,
Fibrinogen and smoking status).” The authors conclude that “an elevated
Blood viscosity
level oflipoprotein(a) is a strong risk factor for CHD in patients
with familial hypercholesterolemia, and the increase in risk is
Increase beneficial and/or protective factors independent of age, sex, smoking status, and serum levels of
Prostacyclin formation (PGI2 + PGI3)
total cholesterol.” In another study on apo A and ischemic heart
Leukotriene B5 (LTB5)
disease in familial hypercholesterolemia, Wikiund et al (119)
Interleukin 2 (IL-2)
also concluded that Lp(a) is a genetic trait that may be useful
Endothelial-derived relaxing factor (EDRF)
Fibrinolytic activity
in identifying patients with familial hypercholesterolemia at high
Red-cell deformability risk for CHD (1 19). Clinical investigations are urgently needed
High-density lipoprotein (HDL) to determine if lowering Lp(a) by w3 fatty acids lowers the risk
for CHD in these patients.
* Reproduced with permission from reference 29.
Additional effects
Effects on lipoprotein (a) Omega-3 fatty acids have been shown in human monocytes
Lipoprotein (a) [Lp(a)] is a genetically determined protein to inhibit the production of platelet activating factor (PAF). One
that has atherogenic and thrombogenic properties. The molecular of the adverse effects of PAF is the activation of platelets, thus
structure ofLp(a) apoprotein is strikingly similar to that of plas- contributing to atherogenesis (120). lnterleukin and tumor ne-
minogen. Omega-3 fatty acids were reported to inhibit the in- crosis factor (TNF) are reduced by feeding fish-oil supplements
hibitor of plasminogen activator and thus contribute to fibri- to humans (121). Both interleukin 1 (IL-I) and TNF are con-
nolysis (97). Thus it was only natural to test the effects of w3 sidered atherogenic because they stimulate the synthesis of
fatty acids on Lp(a) concentrations ( 1 1 5). Herrmann et al (1 15) adhesion molecules, thus causing monocytes to adhere to en-
reported on such a study at the poster session of the NATO dothelial cells. They also activate platelets, neutrophils, and
Advanced Research Workshop on Dietary w3 and w6 Fatty Ac- monocytes (121).
ids: Biological Effects and Nutritional Essentiality. These inves- In conclusion, many studies indicate that w3 fatty acids appear
tigatons studied 62 male patients who had myocardial infarction to decrease or inhibit risk and precipitating factors in the de-
6 mo before the study. Ingestion of fish oil reduced the concen- velopment of CVDS. These factors are summarized in Table
tration of triglycerides, reduced blood pressure, and led to a 6(29).
significant reduction in Lp(a). This study provided the first ev- The new findings in relation to interleukin metabolism and
idence that w3 fatty acids lowered Lp(a). Recently, Schmidt et gene expression indicate that, in addition to their major effects
al (1 16) showed that w3 fatty acids lowered serum Lp(a) con- on prostaglandin metabolism, w3 fatty acids have other far-
centrations when Lp(a) concentrations were > 200 mg/L but reaching effects on intracellular cell communication. These
had no effect < 200 mg/L. findings indicate that it is very important to know and eventually
More recently, Kostner and Herrmann (1 17) compared the understand the numerous inter- and intracellular factors that
effects offish-oil concentrate (12 g FENICO#{174}/d, containing 70% are influenced by w3 fatty acids as well as the specific mechanisms
w3 PUFAs) in 35 patients with coronary disease and a control involved. It is this type of information that will enable us to
group receiving an equivalent amount ofrapeseed oil. In addition design appropriate clinical trials to precisely define the dose of
to measuring Lp(a), these investigators carried out standard (&,3 fatty acids to be utilized and the type of fatty acid and length
plasma lipid and lipoprotein determinations and hemostatic in- ofintervention required for effective therapy while avoiding any
dices. Plasma Lp(a) concentrations were reduced in the fish-oil possible adverse reactions.
TABLE 7 most-important paper on atherosclerosis entitled “Atheroscle-

Genetic determinants and environmental risk factors for CHD* rosis: A problem ofthe biology ofthe arterial wall cells and their
interaction with blood components,” in which the modern con-
Genetic determinants
cepts of atherosclerosis were presented. Ross in 1986 (126) and
Family history ofCHD at an early age
Total serum cholesterol, LDL, and apo B concentrations Steinberg et al in 1989 (127) updated the concepts ofthe response
HDL cholesterol, apo A-I, and apo A-Il concentrations to injury hypothesis in the pathogenesis ofatherosclerosis, which
Lp(a) can be summarized as follows. The first step in the formation
LDL receptor activity of atherosclerosis is a nonspecific (functional) injury to endo-
Thrombosis and coagulation variables thelium followed by an accumulation of monocytes and mac-
Triglycerides and VLDL concentrations rophages, foam cell formation, and platelet aggregation. The
RFLPs in DNA at the apo A-I/apo C-Ill and apo B loci platelets release growth factor, which leads to smooth muscle
Other DNA markers migration and proliferation. At this point cholesterol is deposited
Blood pressure
in the smooth muscle cells and monocyte macrophages in the
Diabetes
vessel wall. These events further lead to the formation of ground
Obesity
Insulin concentration and insulin response substance and eventually to plaque formation. As seen in Table
Heterozygosity for homocystinuria 6, w3 fatty acid ingestion may be able to prevent the increase in
Environmental risk factors cellular components generated by these cells and interfere at
Smoking many steps in the development of the atherogenic process (Fig
Sedentary lifestyle (lack of aerobic exercise) 6) (27, 48).
Diet (excess energy intake) Vegetable oils rich in the w6 LA have been promoted as low-
High saturated fatty acid intake ering blood cholesterol concentrations of people in the United

Low w3 fatty acid intake
States. So much emphasis has been put on the lipid hypothesis
Psychosocial factors
and on lowering serum cholesterol concentrations through diet
Type A personality
and drugs that the contributions ofinflammation and thrombosis
Social class
in the development of CHD have not been fully appreciated.
C Reproduced with permission from reference I 23. An increase in our understanding of the pathophysiology of
coronary artery thrombosis has led to the hypothesis that pre-
venting platelet activation and aggregation are essential steps in
the prevention of coronary thrombotic complications. Current
Cornary heart disease
evidence suggests that the pathophysiology of unstable angina
Much more is known about the effects of w3 fatty acids on involves platelet recruitment and thrombosis. Burr’s study re-
CVD than on any other disease entity. CHD is a multifactorial ferred to earlier (23) is the first prospective dietary-intervention
disease with genetic determinants that interact with many en- trial for secondary prevention ofCHD that demonstrates clinical
vironmental factors, including diet and other lifestyle changes benefit in those given advice to eat fatty fish or fish-oil capsules.
that contribute to its development. All the hyperlipoproteinemias Omega-3 fatty acids alone clearly will not lead to the universal
described so far have a significant genetic component. It has eradication of atherosclerosis. However, it is increasingly evident
been estimated that 50% of the variance in serum cholesterol that dietary fish-oil supplementation may help in the prevention
concentration and 15% of the variance in the fibrinogen con- of atherosclerosis or its thrombotic complications. The favorable
centration are due to genetic factors. effects shown by DeCaterina et al (104) provide further support
An extensive array of genes involved in normal regulation
and function of the cardiovascular system have been identified
with modern genetic techniques [DNA markers, restriction- - - -*“Endothelial Injury”
fragment-length polymorphisms (RFLPs) and in situ hybridiza-
tion studies]. These new genetic markers are being used to predict /
/
Platelet Aggregation
/
risk for CHD, a most important aspect for developing strategies I
for the prevention

in childhood
constitutes
and
a very
ofCHD.
young
powerful
The
adult
health
early identification of individuals
life who are at high genetic
care strategy
risk
for the prevention
I/I
I Monocytes
(circulating) /X//
PDG Factor Thrombosis
_________1 - - -* Fibrinol,sis
ofCHD. Common genetic lipoprotein disorders associated with I M . Smooth musde

(ma6a,aI
premature CHD include familial combined hyperlipidemia
-
I
f
(15%), familial hypentriglyceridemia (5%), and familial hyper-
cholesterolemia
dom,
(5%)
5 g MaxEPA#{174} (1 8% EPA,
( I 22) (Table 7) ( 123).
I 2% DHA)
In the United
twice a day
King-
has been
‘\
\ Earliest
. L.
Atherosclerotic Lesson + LDL
.
Iholesterol
approved for the treatment of severe hypertriglyceridemia in \

\ \ \ Foam Cells + Connective Tissue + Thrombosis
patients at risk of ischemic heart disease or pancreatitis.
Atherosclerosis is a complex disease of the arteries and the
arterial wall. Many cellular biochemical and physical compo-
nents interact at and within the arterial wall. The cellular dy- ------ Atheroma
namics in atherosclerosis were reviewed by Faggiotto ( 124) who FIG 6. Sites of potential interventions for preventing development of
states that “atherosclerosis encompasses a number of pathological atherosclerosis. Note that several of these possibilities would abort the
processes and has many ofthe features ofdegenerative disorders, disease before the concentration of plasma LDL cholesterol could con-
inflammation and neoplasia.” In 198 1 Ross (125) published a tribute to the atherosclerotic process. Reproduced from reference 48.
450 SIMOPOULOS
that w3 fatty acids could modify the occurrence and the course TABLE 8
of atherosclerosis. Ethnic differences in fatty acid concentrations in thrombocyte
Recently, Dolecek and Grandits (20) investigated the 24-h phospholipids and frequency of cardiovascular disorders
dietary-recall data in the usual-care group of the Multiple Risk
Europe, Greenland
Factor Intervention Trial and distinguished between w3 and t6
United States Japan Eskimos
fatty acid intake and their relationship to four mortality cate-
gories: CHD, total CVD, all-cause mortality, and cancer. Analysis Arachidonic acid,
of the combined fatty acids predominantly found in fish (EPA C20:4w6 (%) 26 21 8.3
and DHA) demonstrated significant inverse associations with Eicosapentaenoic acid,
C20:5w3 (%) 0.5 1.6 8.0
CHD, CVD, and all-cause mortality groups. The benefit ap-
w6:w3 50 12 1
peared to be in the highest intake quintile with a mean ingestion
Cardiovascular mortality
of -664 mg/d of EPA and DHA. When compared with zero
(%)t 45 12 7
intake, mortality from CHD, CVD, and-all cause mortality was
40%, 41%, and 24% lower, respectively. An inverse association a Adapted from reference I 28.
was noted between the ratio of 18:3w3 to 18:2w6 and cancer t Percent ofall deaths.
mortality. Thirty-three percent fewer cancer deaths occurred in
the highest intake quintile when compared with the lowest.
Populations with high consumption of fish, such as the Es- pressure. Many studies since then have used w3 fatty acids in
kimos and Japanese, have lower rates of myocardial infarction the form of fish oils with similar results in normal and hyper-
(Table 8) (128). The epidemiologic studies of Kromhout et al tensive subjects (72, 1 33-137) but not in all intervention trials
(1 7) and the intervention studies of Burr et al (23) showed a (138, 139).

decrease in CHD mortality in people consuming relatively small More recently Knapp and FitzGerald (1 35) reported on a
amounts of fish (0.5 g w3 fatty acids/d or 1 .5 g fish oil/d) over controlled study of PUFA supplements in essential hypertension.
a long period of time (19 y and 2 y, respectively). This suggests These investigators studied blood pressure and eicosanoid pro-
that small doses over long periods of time may have beneficial duction during supplementation of dietary fat for 4 wk in 32
effects, possibly by reducing blood pressure and other risk factors. men with mild essential hypertension. Groups ofeight subjects
Certainly more studies are needed to define the precise dose of received either 3 or 1 5 g w3 fatty acids/d in the form of 10 or
w3 fatty acids based on the total long-term diet of the subjects 50 mL MaxEPA#{174}, 39 g w6 fatty acids/d in the form of 50 mL
in terms of w3, w6, w9, and saturated fatty acids. The unique safflower oil, or 50 mL/d of an oil mixture that approximated
pharmacokinetics of w3 fatty acids in terms of time and dose- the types offat present in the American diet. Urinary metabolites
dependent accumulation in cell membranes should help define were measured to assess biosynthesis of eicosanoids. The men
the optimum amount ofw3 fatty acids and length oftime of the who received the high dose of fish oil had a mean decrease in
intervention. systolic blood pressure of6.5 mm Hg and a decrease of4.4 mm
The vast majority of survivors of myocardial infarction have Hg in diastolic blood pressure. The group receiving the low dose
one or more of four lipoprotein abnormalities. These include of fish oil (10 mL/d) did not have any significant change in
increased LDL-cholesterol concentrations, decreased HDL- blood pressure from baseline during the supplementation period
cholesterol concentrations usually accompanied by increased nor did the u,6-supplemented on the control groups. In the group
triglyceride or VLDL concentrations, increased concentration receiving the high dose offish oil, the formation of vasodilatory
of chylomicron remnants and intermediate-density lipoprotein prostacyclins (PG!2 and PGI3) increased initially but this increase
(IDL), and the presence in plasma of increased concentrations was not maintained as blood pressure fell. The concentration of
of Lp(a). The exact mechanism whereby each of these abnor- thromboxane A2 metabolites fell and metabolites of thrombox-
malities causes CHD is an area of active investigation and the ane A3 were detected in the groups receiving fish oil. The for-
genetic contribution to each ofthese abnormal lipoprotein phe- mation ofPGE2 increased during supplementation with safflower
notypes is coming into focus (129). As we begin to unravel the oil and tended to decrease with fish oil but no POE3 metabolite
genetics of atherosclerosis and identify individuals with genetic was detected. These data indicate that high doses of fish oil can
susceptibility to CHD, modification ofdiet early in life and the reduce blood pressure in men with essential hypertension.
provision of increased amounts of w3 fatty acids should be ben- Bonaa et al ( 140), in a population-based intervention trial
eficial in the prevention of CHD. from Troms#{248},recently reported decreases of6 mm Hg in systolic
blood pressure and 3 mm Hg in diastolic blood pressure with
fish-oil supplementation. These investigators monitored diet and
Hypertension
assessed concentrations of plasma phospholipid fatty acids to
Hypertension is also a multifactorial disorder involving gene- determine the relation among diet, fatty acids, and blood pres-
nutrient interactions and other factors (1 30). Different mecha- sure. Dietary supplementation with fish oil did not change mean
nisms appear to be involved, operating at variable proportions blood pressure in the subjects who ate fish three or more times
based on the organ involved or the cause of hypertension. per week as part oftheir usual diet or in those who had a baseline
Changes were reported in eicosanoid metabolism, renin con- concentration of plasma phospholipid o3 fatty acids > 175.1
centrations, vascular reactivity, blood viscosity, loss of sodium, mg/L, suggesting that a relationship may exist between plasma
increase in potassium in cells, and a decrease in intracellular phospholipid w3 fatty acid concentration and blood pressure.
calcium, among others (130). There was a lower blood pressure at baseline in subjects who
In 1983 two groups of investigators, Singer et al (1 3 1) and habitually consumed larger quantities of fish, suggesting that
Lorenz et al (1 32), were the first to show that adding mackerel supplementation with fish oils would be important from the
to the diet ofpatients with mild hypertension lowered the blood primary prevention standpoint. In another study, three cans of
mackerel per week (equivalent to 1 .2 g w3 fatty acids/d or 1.2 DHA. The anti-inflammatory effects of fish oils are partly me-
x 3 = 3.6 g of fish oil/d) for 8 mo led to lowering of blood diated by inhibiting the 5-lipoxygenase pathway in neutrophils
pressure (1 33). This amount of fish oil could be considered ac- and monocytes and inhibiting the leukotriene B4 (LTB4)-me-
ceptable for a daily intake by the general population. diated function of neutrophils while increasing the production
It was suggested that these effects on blood pressure during of LTB5 (Fig 7) ( 1 53, 1 54). Studies since 1985 show that w3
dietary supplementation with w3 fatty acids are due to changes fatty acids influence interleukin metabolism by decreasing IL-l
in the endogenous synthesis of vasoactive eicosanoids. Two re- (121, 155, 156).
search groups showed that dietary EPA is converted to PGI3 in Many experimental studies have provided evidence that in-
man and does not suppress formation of PGI2 from AA (141, corporation of alternative fatty acids into tissues may modify
142). Other possible mechanisms under consideration include inflammatory and immune reactions and that w3 fatty acids in
effects of w3 fatty acids on renal function, a lowering of blood particular are potential therapeutic agents for inflammatory dis-
viscosity, and a reduction in vascular responsiveness to systemic eases.
vasoconstrictors ( 143). Lorenz et al ( 1 32) observed an increase
in urinary sodium and a decrease in plasma renin activity at the Arthritis
end ofthe fish-oil period in a group of men whose Western diet
was supplemented with cod-liver oil. Fish-oil supplements were Advances in the understanding ofleukotriene metabolism and
reported to have beneficial effects on the blood pressure of pa- its role in inflammation and autoimmune disorders began to
tients on hemodialysis with little residual function (144). Normal attract investigators who used fish oils in patients with arthritis
subjects do not show any change in renal function even when with promising results (1 54). In normal volunteers, marine lipids
given pharmacologic doses offish oil, which is encouraging from suppress 5-lipoxygenase pathway products from both neutrophils
the safety standpoint (145). and monocytes and they also suppress production of PAF from

Rats with reduced renal function (subjected to subtotal ne- monocytes ( 1 20). In addition, the chemotactic response of neu-
phrectomy) given dietary fish oil had reduced urinary PGE and trophils to transmembrane agonists is suppressed by dietary fish
renal function along with increased proteinuria and mortality oils. In patients with rheumatoid arthritis, inhibition of 5-lipox-
(146). As indicated earlier, studies from rats cannot be extrap- ygenase products are limited to LTB4 , suggesting inhibition of
olated to humans because rats do not make PGI3 (107-109). the epoxide hydrolase step, and neutrophil chemotaxis is in-
The effects of c,3 fatty acids on immune-mediated renal dys- creased by the fish-oil dose rather than suppressed as in normal
function are complex. Kelley et al (147) showed that fish oils subjects. These differences between normal subjects and patients
prolong the survival in mice that develop lupus nephritis whereas with arthritis could be related to specific alterations ofthe disease
Westberg et al (148) found less benefit. However, Kelley used a or to medications taken by patients (156). Omega-3 fatty acids
larger dose of fish oil. In humans the clinical course of lupus were shown to decrease IL- 1 in animals and in patients with
nephritis did not improve with fish-oil supplementation (149, rheumatoid arthritis and normal volunteers (121, 1 55, 156).
150). More clinical investigations are needed before any con- Kremer et al ( 1 55) carried out a prospective randomized dou-
clusions can be drawn. ble-blind, placebo-controlled parallel study. Three groups were
Recent data on the additive effects offish-oil supplements and studied for 24 wk with two different doses of fish oil and one
propranolol were presented at the Second International Con- dose of olive oil, and clinical and immunological indices were
ference on the Health Effects ofOmega-3 Polyunsaturated Fatty measured. As in previous studies there was clinical improvement
Acids in Seafoods (1 5 1). The combination ofw3 fatty acids and and, in addition to the decrease in LTB4 and increase in LTB5,
propranolol potentiated their blood-pressure-lowering effects. there was a significant decrease in IL-l production and a non-
In addition, the increase in plasma triglycerides often seen during significant increase in IL-2. LTB4 exerts a positive modulating
antihypertensive therapy did not occur. Therefore, c,3 fatty acid effect on the genetic control ofIL-1 probably at the translational
supplementation has the potential for a beneficial modification level within the cytoplasm. These findings were confirmed by a
of several cardiovascular risk factors as adjuvants to the anti- number of other investigators. Omega-3 fatty acids (fish oil), as
hypertensive regimen. a dietary supplement, along with nonsteroid antirheumatic drugs
were shown to provide subjective relief to patients with rheu-
Inflammatory and autoimmune disorders matoid arthritis.
The effects of supplementing the diet with w3 fatty acids in Psoriasis

the form of fish oils on the function of the 5-lipoxygenase path-
ways of peripheral blood polymorphonuclear leukocytes and The recognition that AA metabolism is altered in psoriasis
monocytes has been investigated in normal subjects and in pa- prompted attempts to inhibit the generation of proinflammatory
tients with diseases such as arthritis, psoriasis, ulcerative colitis, lipoxygenase products [LTB4 and l2-hydroxyeicosatetraenoic
lupus erythematosus, and asthma. These studies were stimulated acid (12-HETE)J, which are markedly elevated in the psoriatic
by the demonstration by Prickett et al (1 52) that the fatal spon- lesions (1 57). The addition of MaxEPA#{174} to the standard treat-
taneous autoimmune renal disease in a genetic strain of NZB ment produced further improvement and a decrease in LTB4
mice can be largely prevented by changing the fat in the diet and 12-HETE (Fig 7) (64). In other studies fish oil was success-
from beeftallow to fish oil. In fact, the protective effect of marine fully used in combination with etretinate to reduce the hyper-
lipids on autoimmune renal disease is one ofthe most dramatic lipidemia caused by that drug and with ultraviolet B (UVB),
effects of w3 fatty acids on any pathology (1 52). Supplementing where it prolongs the beneficial effects ofa course of phototherapy
the diet with w3 fatty acids (3.2 g EPA and 2.2 g DHA) in normal (1 58). Studies of fish oil in combination with cyclosporin are in
subjects increased the EPA content in neutrophils and monocytes progress in an attempt to reduce nephrotoxicity, which is the
more than sevenfold without changing the quantities ofAA and major side effect of that drug (158).
452 SIMOPOULOS
COOH
:::::,c0oH
&A EPA DCI-t4
1
[ UPOX[
5HPE -:PE: THPDCHA t 4HPDCHA
5HETE 5HPE THDcHA ±
1DoDRAsE
__ __ _
6-tmns-LTB4
diastereoisomers
4 LTA4
?:,(, LTA5- 6 tmns-LTB5
diasteresorns

L1C --#{248}’LTD5 -.‘tTE
LTB Lit4 -‘LTD -LTE
FIG 7. Oxidative metabolism of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid
(DCHA) by the 5-lipoxygenase pathway. 5HPETE denotes 5-hydroperoxyeicosatetraenoic acid; 5HETE, 5-hydrox-
yeicosatetraenoic acid: 5HPEPE, 5-hydroperoxyeicosapentaenoic acid: 5HEPE, 5-hydroxyeicosapentaenoic acid:
7HPDCHA, 7-hydroperoxydocosahexaenoic acid: 4HPDCHA, 4-hydroperoxydocosahexaenoic acid; 7HDCHA,
7-hydroxydocosahexaenoic acid: 4HDCHA, 4-hydroxydocosahexanoic acid: and LT, leukotriene. Reproduced with
permission from reference 153.
LIcerativc’ cOlitiS restriction potentiated the effects of w3 fatty acids (160, 161)
whereas w6 fatty acids in the form of corn oil increased tumor
As indicated earlier, LTB4, a metabolite of AA, is produced
formation, size, and number (16 1, 162). It also was shown that
by activated neutrophils, and w3 fatty acids decrease its pro-
c(,3 fatty acids decrease POE2 production in animals fed w3 fatty
duction. LTB4 is an important mediator of inflammation in
acids ( 162). As expected, fatty acid analysis of the transplanted
ulcerative colitis and it is believed to recruit additional neutro-
tumors reflects the specific composition ofthe dietary fat ingested
phils from the bloodstream into the mucosa. Stenson et al (159)
by the host ( 162). Furthermore, these studies indicate that the
conducted a study of the effects of fish-oil supplementation on
composition of dietary lipids modifies lipid metabolism and that
ulcerative colitis. Preliminary analysis showed statistically sig-
high dietary intake of co3 fatty acids can prevent or delay the
nificant improvement in sigmoidoscopy score and global clinical
expression ofthese neoplasms. In other studies involving human
assessment after 4 mo of fish-oil-supplemented diet compared
breast-cancer cells in nude mice, the mice fed w3 fatty acids had
with placebo diet in active ulcerative colitis. This is the first
fewer pulmonary metastases, decreased serum estrogen and pro-
double-blind crossover trial of fish-oil supplementation in ul-
lactin concentrations, less PGE2 in the tumor, and reduced
cerative colitis.
c-mvc oncogene mRNA concentrations in the tumor-tissue cells
(160). The opposite occurred in the corn-oil-fed mice.
Cancer Animal studies in progress are using fish oils to elucidate the
mechanisms involved, including the changes in prostaglandin
The number ofpublications from the use ofw3 fatty acids in
production, immune function, free radical formation, membrane
cancer studies in animals has increased exponentially over the
fluidity changes, modulation of intracellular transport systems,
past 5 y (29). Animal tumor models in which the tumor was
hormone secretion, calorie utilization, and gene expression ( I 63).
induced by carcinogens and animal models with transplantable
tumors (breast, colon, pancreas, and prostate) have been inves-
Diabetes
tigated. The results have consistently shown that w3 fatty acids
delayed tumor appearance and decreased both the rate of growth Diabetes is a chronic disorder with complications includ-
and the size and number of tumors. In these models calorie ing hypercholesterolemia, hypertriglyceridemia, atherosclerosis,
CHD, and hypertension. Many of these complications are at- in blood pressure that is produced by cyclosporin and, in fact,
tributable to microvascular disease (164). Jensen et al (165), a favorable reduction in thromboxane A2 occurred ( 1 75). There
using a double-blind crossover design, studied the effects on en- were not any adverse effects attributable to the supplements. In
dothelial permeability, blood pressure, and plasma lipids of 8- a randomized controlled study van den Heide et al ( 1 76) inves-
wk supplementation of a diabetic diet with cod-liver oil rich in tigated the effects offish-oil supplements on cyclosporin therapy
(1)3 fatty acids compared with 8-wk supplementation with olive in renal-transplant patients. The fish-oil supplements caused a
oil in 1 8 insulin-treated diabetic patients with albuminuria with significant decrease in renal vascular resistance, increased gb-
> 30 mg/d. The patients receiving cod-liver oil showed a sig- merular-filtration rates, and lowered mean arterial pressure. This
nificant fall in mean transcapillary escape rate ofalbumin corn- is another example of the beneficial effects of w3 fatty acids
pared with baseline and a reduction in mean blood pressure. No combined with drugs in which w3 fatty acids decrease drug tox-
changes occurred with olive oil. Cod-liver oil was associated with icity and also improve the hemoclynamic aspects of illness.
a significant increase in plasma HDL cholesterol, a significant
decrease in the concentration of VLDL cholesterol and triglyc-
eride, and no change in the concentration of LDL cholesterol. Essentiality: the role of w3 fatty acids
Jensen et al concluded that cod-liver oil may have a direct action in growth and development
on vascular permeability that is independent of its beneficial
In parallel with the studies investigating the robe of w3 fatty
effect on blood pressure and postulated that this action results
acids in disease states, an outstanding group ofscientists turned
from a decreased transfer of lipoproteins into the vascular wall.
their attention to the essentiality of w3 fatty acids throughout
In this study blood glucose concentrations were unchanged. In
the life cycle.
other studies the use offish oils in non-insulin-dependent diabetes
mellitus (NIDDM) (166, 167) and in insulin-dependent diabetes

Animal studies
mellitus (IDDM) ( 168) increased blood glucose, glycosylated
hemoglobin, plasma total cholesterol, LDL cholesterol, and Studies in rats and rhesus monkeys showed that dietary re-
serum apo B. The magnitude of these effects is generally small striction of to3 fatty acids (primarily LNA) during pregnancy
and the changes in glucose metabolism are associated with in- and lactation interferes with normal visual function and may
creased hepatic glucose output and impaired insulin secretion even impair learning ability in offspring (177). Connor et al (178)
but unaltered glucose disposal rates. Further studies are needed concluded that w3 fatty acid deficiency in rhesus monkeys is
ofthe fatty acid composition ofphospholipids in diabetic patients characterized by reduced vision, abnormal electroretinograrns
during w3 supplementation under defined conditions of meta- (ERGs), and polydipsia (29). In this model, abnormalities of the
bolic control, diet, and type of NIDDM and IDDM. ERG induced by c3 fatty acid deficiency during development
appear to be irreversible. In 1987 Rotstein et al (1 79) studied
the effects ofaging on the composition and metabolism of DHA-
Omega-3 fatty acids as an adjuvant to drug therapy
containing lipids of the retina in rats. They concluded that an
Omega-3 fatty acids in combination with drugs for the treat- impairment of the -4 desaturase enzyme system is probably
ment ofdiseases is an area ofimrnense interest because it opens responsible for the decreased concentrations of 22:6w3 (and 22:
a new field in nutrition research, w3 fatty acids in the control of 5w6) observed in retinal lipids as a consequence ofaging. Because
metabolic and autoimmune disorders, that includes CVD, ar- DHA is required for normal function of photoreceptors in rats
thritis, lupus erythernatosus, psoriasis, ulcerative colitis, and and primates, it is quite possible that a decrease in DHA plays
cancer. Preliminary data from animal and human studies suggest an important role in visual impairments that accompany old
that the concurrent ingestion or administration ofw3 fatty acids age. Therefore, dietary DHA rather than LNA would be the
with drugs leads to potentiation of drug effects, as with pro- appropriate co3 fatty acid to use in studies aiming to influence
pranolol (1 5 1), which may lead to a decrease both in the dose the development ofvisual impairments and even improve visual
of o3 fatty acids and in the drug dose or, as with cyclosporin function in elderly people.
(1 58), to a decrease in toxicity ofthe drug. By partially replacing
Human studies
the fatty acids of phospholipids in the cell membranes, w3 fatty
acids modify enzymes, receptors, and other proteins (29). Ad- Pregnancy. The role of w6 and w3 fatty acids in pregnancy
ditional studies suggest that the incorporation of w3 fatty acids has been examined only recently in humans. Over the past 50
by cell membranes is enhanced in the presence of olive oil and y the influence of maternal nutrition on fetal growth has been
linseed oil, emphasizing once again the importance of nutrient- extensively studied in the context ofprotein-caborie malnutrition.
nutrient interactions (169). In 198 1 Crawford et al ( 1 80) calculated the LA and LNA re-
Cyclosporin is used widely in organ transplantation and in quirements for pregnancy to be ‘- 1% ofthe nonpregnant worn-
many individuals its use leads to impairments in renal function an’s dietary energy and the AA and DHA requirements to be
(1 70) and increased thromboxane formation (1 7 1). It was noted another 0.5%.
that the use of fish oil instead of olive oil as the vehicle for its Fetal development, human milk, and infint /i’eding. As far
administration in rats led to attenuation of the cyclosporin back as 1973, Crawford et al (1 8 1) analyzed 32 samples of human
nephrotoxicity ( 172) without affecting thromboxane synthesis milk and found that it contained LA, AA, LNA, EPA, and DHA
(173). These findings led to the use of 3.6 g EPA/d and 2.4 g and recommended their inclusion in infant formula. Infant for-
DHA/d in patients with psoriasis who were taking cyclosporin: mula does not contain AA, EPA, or DHA (Table 9) (35).
there was a decrease in the decline in renal function without EPA and DHA are higher in the erythrocytes of breast-fed
cyclosporin pharmacokinetics being affected ( 1 74). In another infants than in those of bottle-fed infants (182). The milk of
patient who had received a renal transplant, a low dose of w3 vegan women contains lower concentrations of DHA than does
fatty acids (1 .5 g EPA/d) did not lead to the expected increase the milk of omnivores and this difference is reflected in the
454 SIMOPOULOS
TABLE 9
Fatty acid composition of human milk and formulas (molar percent)*
Fatty acidt Human milk (n = 1 1) Portagen#{174}4 Enfamil Premature#{174}4 Similac Special §

Care#{174}
8:0 (caprylic acid) 0.3 60 24.5 24.1

10:0 (capric acid) 1.4 24 14.1 17.7
12:0 (lauric acid) 7.0 0.42 12.2 14.9
14:0(myristicacid) 8.0 Trace 4.7 5.8
l6:0(palmiticacid) 19.8 0.19 7.5 6.8
16:1 (palmitoleic acid) 3.2 0.1 0.2
18:0(stearicacid) 5.9 0.47 1.7 2.3
18:1 (oleicacid) 34.8 4.1 12.4 10.0
I8:2w6 (linoleic acid) 16.0 8.1 22.4 17.4
I 8:3w3 (s-linolenic acid) 0.6 Trace 0.6 0.9
20:1 (gondoic acid) 1.1 0.3 0.1
20:2w6 0.6
20:3w6 (dihomo-y-Iinolenic acid) 0.4
20:4w6 (arachidonic acid) 0.6
2O:5w3 (eicosapentaenoic acid) 0.0
22:1 (docosenoicacid) 0.1
22:4w6 (docosatetraenoic acid) 0.2
22:5w6 (docosapentaenoic acid) 0.2

22:5w3 (docosapentaenoic acid) 0.1
22:6w3 (docosahexaenoic acid) 0.2
a Reproduced with permission from reference 35.

t Common name in parentheses.
4 Values from Pediatric Products Handbook, 1983 Edition, Mead Johnson Nutritional Division, Evanston, IN.
§ Ross Laboratories. Columbus, OH.
erythrocytes of their infants. After birth there is a decrease in tissues, and 3) response to injury to the nervous system (ischemia
the DHA content of erythrocytes of full-term and premature and convulsions) and also during retinal stimulation, both of
infants (42. 183). Infants born at term and fed mother’s milk which trigger the release ofDHA from membrane phosphobipids;
had approximately twice as much DHA in erythrocyte phos- some ofthis DHA may be peroxidated or lost through washout
pholipids as did infants fed formula containing LNA but not to the blood and may need to be replenished (199).
DHA. Because the greatest amount ofDHA accumulation occurs Bourre et al (193) showed that the brain of the w3-deficient
during the last trimester of pregnancy, the amount of DHA rat is more susceptible to environmental toxins and alcohol.
available to premature infants assumes critical importance. In It is now well recognized that nutrition during the first weeks
1987 Liu et al (184) determined that 11 mg DHA-kg’-d’ of life can have a decisive influence on brain development. Be-
added to formula resulted in 0.2% DI-IA in the total dietary fatty cause fatty acid patterns ofall organs change during development,
acids in the formula. which is within the range ofO. 1-0.3% found it is necessary to know the normal profiles during the various
in human milk. The inclusion of0.2% DHA in the formula did stages of development to understand the role of nutritional in-
not decrease plasma AA and appeared to be a physiological fluences.
amount that could prevent declines in membrane DHA of pre- Martinez ( 185) studied the composition of w3 and w6 fatty
mature infants. acids in brain, liver, and retina in human fetuses during the last
A major question remaining is to what degree the fatty acid trimester of pregnancy. After 30 wk gestation there is a prefer-
pattern in erythrocytes reflects the neural status of w6 and w3 ential desaturation ofthe long-chain w3 fatty acids in the brain.
metabolites in humans. The liver shows a similar profile. In both tissues, 22:6w3 increases
The effects of PUFA deficiency on the developing brain have quadratically and 20:4w6 and 18: lw9 decrease linearly in phos-
been widely documented in experimental animals whereas in- phatidylethanolamine (PE). In the retina, as in the forebrain and
formation from humans is scarce. However, work by Martinez the liver, the proportion ofw3 fatty acids increases whereas that
et al ( 185- 1 88), Innis ( 189), Carlson ( 190), Neuringer et al (191, of w6 fatty acids decreases throughout development. These
192), and Bourre et al ( I 93) has added considerably to our changes can be clearly illustrated by using the ratio of 22:6w3
knowledge, much of which was pioneered by Lamptey and to 20:4w6. In the human retina this ratio doubles between 24
Walker ( 194), Walker ( 195), Wheeler et al ( 196), Crawford et al wk of gestation and term and continues to increase with age.
(197), and Clandinin et al(198). These findings should be the guidelines for the feeding of pre-
During l8:3w3 dietary deprivation, DHA is replaced by 22: maturely born infants.
5w6 in the retina and brain of animals. Replacement with 22: Martinez and Ballabriga (1 87) also investigated the liver and
5w6, the fatty acid most closely resembling DHA, suggests ac- forebrain of infants who had received total parenteral nutrition
tivation of a cellular compensatory mechanism. The w3 fatty high in linoleate (Intralipid#{174}) for 4-12 d. At autopsy a signifi-
acids are required by the membranes ofphotoreceptor cells and cantly lower-than-normal proportion of 22:6w3 was found in
synapses for 1) synaptogenesis and photoreceptor membrane liver phosphoglycerides. There were a number of other changes
biogenesis during the perinatal period, 2) normal functioning of in long-chain PUFAs and high concentrations of 1 8:2w6 that
(1)3 FATTY ACIDS IN HEALTH AND DISEASE 455
were not consistent with the values noted in normal fetal de- Dietary implications
velopment.
Martinez’s ( I 85) findings in the retinas of two postnatally Omega-3 and 6 PUFAs are two classes of EFAs that are not
malnourished infants were similar to those described in the liver interconvertible and that constitute a significant part of practi-
ofchildren receiving high intravenous doses of 18:2w6. One of cally all cell membranes. Whereas cellular proteins are genetically
the malnourished children had mucoviscidosis. Both children determined and control important cellular functions indepen-
had unusually high concentrations of22:5w6 in retina and phos- dently ofdietary intake, the lipid composition ofcell membranes
phatidylcholine as a sign of DHA deficiency. One premature is dependent to a great extent on the composition of the diet.
infant (25 wk gestation) had received commercial milk formulas When ingested, fatty acids such as EPA and DHA are incor-
with w6:w3 varying between I 8: 1 and 66: 1 during the first 4 mo porated into the sn-2 position in cell membrane phospholipids,
oflife. The retina ofthis infant was very deficient in 22:6w3. displacing AA. Because the fatty acid composition ofcell mem-
It can be concluded that diets with a high w6:w3 can be con- branes modulates important cell functions and because the fatty
sidered unbalanced relative to human breast milk and that these acids in membranes are dependent on dietary intake, it is obvious
diets are damaging to the PUFA composition ofthe developing that in referring to PUFAs it is essential to distinguish between
central nervous system in humans. Martinez ( 1 85) stated that w3 and co6 fatty acids in making dietary recommendations. Sim-
“when high doses of l8:2w6 are given intravenously, the inhib- ply using the P-S ratio ofpolyunsaturated fatty acids to saturated
iting effect on the series is very strong. even with a theoretically fatty acids (P:S) ratio is inappropriate and inadequate on the
correct omega-6:omega-3 ratio, probably because substrate in- basis of the knowledge we have today.
hibition adds to competition between families of fatty acids for Many dietary studies and interventions have been carried out
the desaturase systems. This should serve as a warning against and dietary recommendations have been made in relation to
saturated fatty acids and cholesterol. However, the amount of

manufacturing such unphysiobogical fatty acid mixtures for use
in pediatric nutrition.” o,3 fatty acids in the diet and their effects on health and disease
Carlson ( 190) showed that membrane 22:6w3 was highest at have not yet been considered in the development of dietary
birth and declined with time in formula-fed infants and that fish guidelines by national governments except for the most recent
oil could be used as a source of 22:6w3 in the range found in Canadian Nutrition Recommendations (Table 10) (203). Be-
cause w3 fatty acids have different metabolic effects than do w6
human-milk-fed infants. One month after delivery, preterm in-
fatty acids and because w3 fatty acids are essential for normal
fants not fed human milk had plasma phospholipid 22:6w3 more
growth and development and for overall health, accurate knowl-
like that of monkeys fed safflower oil, and the bow concentrations
edge ofthe amount and type ofw3 fatty acids in foods is essential.
seen in premature infants are analogous to those at which de-
Both terrestrial and marine sources ofw3 fatty acids are impor-
monstrable deficits in visual acuity occur in infant monkeys.
tant in this regard.
Uauy et al (200) showed that premature infants fed formulas
It is now accepted that it is important to consider the functions
with a high ratio of LA to LNA (30: 1) have poorer ERG re-
ofthe different types offatty acids (w3, w6, and w9) rather than
sponsiveness early in infancy than do those fed human milk or
simply total fat (percentage ofcalories from fat) or the amount
formula with a lower ratio of LA to LNA (9: 1). The addition of
ofpolyunsaturates. The question is not simply about the P:S in
fish oil further improved some ERG responses. Visual-acuity
the diet but about the concentrations of the w3, w6 polyunsat-
development was improved by fish-oil supplementation of for-
urated, and w9 monounsaturated fatty acids relative to saturated
mula during the first half of infancy compared with formula
fatty acids in the diet. Fatty acids should be considered in terms
containing 1 .5-2.5% ofenergy as LNA. These data strongly sug-
of their overall metabolic effects in growth and development
gest that DHA is essential for the functional development of the
and for their effects on serum lipids, inflammation, thrombus
eye and brain of premature infants.
formation, and tumor development. Trans fatty acids were re-
Children, adults, and elderly adults. Omega-3 fatty acid de-
cently shown to elevate serum cholesterol (52). Stearic acid
ficiency was originally reported by Holman et al (201) in a young
formed during hydrogenation does not raise cholesterol but it
child. Subsequently Bjerve et al (202) reported w3 fatty acid
increases the risk ofthrombosis (204). Clearly there is a need to
deficiency in a child and in a group ofelderly patients in nursing define precisely the functions of the various fatty acids.
homes who were fed orally for several years by gastric tube with Because ofthe increased amounts ofc,6 fatty acids in our diet,
diets containing very low amounts of w3 fatty acids. Studies the eicosanoid metabolic products from AA, specifically pros-
based on clinical findings and determinations of plasma and taglandins, thromboxanes, leukotrienes, hydroxy fatty acids, and
erythrocyte lipids after dietary supplementation with soya and lipoxins, are formed in larger quantities than those formed from
cod-liver oil strongly suggest that the patients had w3 fatty acid fatty acids, specifically EPA. The eicosanoids from AA are
deficiency. These patients represent the first adults and the second biologically active in very small quantities and ifthey are formed
child described with w3 fatty acid deficiency. The results indicate in large amounts they contribute to the formation of thrombus
that w3 fatty acids are essential for normal growth and cell func- and atheroma; to allergic and inflammatory disorders, particu-
tion in humans in ways similar to those in several animal species. larly in those who are susceptible: and to proliferation of cells.
Assuming linear relationships between dietary intake of w3 Thus a diet rich in w6 fatty acids shifts the physiological state
fatty acids and the measured concentrations ofw3 fatty acids in to one that is prothrombotic and proaggregatory with increases
plasma and erythrocyte lipids, the optimal intake of 1 8:3w3 has in blood viscosity. vasospasm. and vasoconstriction and decreases
been estimated to be 800-1 100 mg/d whereas the optimal intake in bleeding time. Bleeding time is decreased in groups of patients
of very-long-chain w3 fatty acids was estimated to be 300-400 with hypercholesterolemia (205), hyperlipoproteinemia (206),
mg/d ( 1 15). It is suggested that the dietary requirements of w3 myocardial infarction (207, 208) and other forms of atheroscle-
and w6 fatty acids should be stated in milligrams or grams per rotic disease (209), and diabetes (obesity and hypertriglycerid-
day and not only as a percent of energy. emia). Bleeding time is longer in women than in men and longer
456 SIMOPOULOS
TABLE 10
Summary ofexamples ofrecommended nutrients based on energy expressed as daily rates5
Age and sex Energy Thiamin Riboflavin Niacin w3 PUFAs w6 PUFAs
Mi (keal) mg mg NEf g g
0-4 mo (M, F) 2.51 (600) 0.3 0.3 4 0.5 3

5-12 mo (M. F) 3.77 (900) 0.4 0.5 7 0.5 3
I y (M. F) 4.60 (1 100) 0.5 0.6 8 0.6 4
2-3 y (M. F) 5.44 (1300) 0.6 0.7 9 0.7 4
4-6y(M.F) 7.53(1800) 0.7 0.9 13 1.0 6
7-9 y
M 9.20 (2200) 0.9 1.1 16 1.2 7
F 7.95(1900) 0.8 1.0 14 1.0 6
10-12 y
M 10.5 (2500) 1.0 1.3 18 1.4 8
F 9.20(2200) 0.9 1.1 16 1.1 7
13-15 y
M ll.7 (2800) 1.1 1.4 20 1.4 9
F 9.20 (2200) 0.9 1.1 16 1.2 7
16-18 y
M 13.4 (3200) 1.3 1.6 23 1.8 11
F 8.79 (2100) 0.8 1.1 15 1.2 7

19-24 y
M 12.6 (3000) 1.2 1.5 22 1.6 10
F 8.79 (2100) 0.8 1.1 15 1.2 7
25-49 y
M 11.3 (2700) 1.1 1.4 19 1.5 9
F 8.37(2000) 0.8 1.0 14 1.1 7
50-74 y
M 9.62 (2300) 0.9 1.3 16 1.3 8
F 7.53(1800) 0.84 1.04 144 1.14 74
75+ y
M 8.37 (2000) 0.8 1.0 14 1.0 7
F 7.11 (1700) 0.84 1.04 144 1.14 74
Pregnancy (additional)
1st trimester 0.42 ( 100) 0. 1 0. 1 0. 1 0.05 0.3
2nd trimester 1.26 (300) 0.1 0.3 0.2 0.16 0.9
3rd trimester 1.26 (300) 0.1 0.3 0.2 0.16 0.9
Lactation (additional) 1.88 (450) 0.2 0.4 0.3 0.25 1.5
S From reference 203.

t Niacin equivalents.
4 Value below which intake should not fall.
§ Assumes moderate physical activity.
in young than in old people. There are ethnic differences in intervention, that the risk of bleeding for a given bleeding time
bleeding time that appear to be related to diet. The increase in is independent ofthe cause ofthe prolongation, or that bleeding
bleeding time brought on by the ingestion of fish or fish oils is from the skin can predict bleeding elsewhere in the body (for
an attempt to return to a more physiological state. example, duration of bleeding from a skin wound does not cor-
Bleeding time is determined by platelet function, local tissue relate with duration ofbleeding from a gastric biopsy site). There
factors, and components of the coagulation system. Rodgers and is no evidence that the bleeding time is useful for monitoring
Levin (2 10) carried out a critical reappraisal ofthe bleeding time the effects of hemodialysis or transfusion therapy.”
and concluded that there is no evidence that bleeding time is a Evidence that long-chain w3 fatty acids protect against the
predictor of hemorrhage risk and summarized their findings as development of CVD continues to accumulate from epidemi-
follows: “The pathophysiobogy of an abnormal bleeding time obogic surveys, animal-feeding studies, biochemical research, and
remains poorly understood. The bleeding time is affected by a human clinical trials and intervention studies. Most investigators
large number of diseases, drugs, physiologic factors, test con- advise that addition of fish to the diet several times weekly may
ditions, and therapeutic actions, not all ofthem platelet-related. be ofbenefit in preventing CHD. There is insufficient evidence
The test is likely to remain widely used for the diagnosis of to quantify the exact prophylactic benefit. Yet the epidemiologic
inherited disorders of platelet function, such as von Willebrand’s evidence from the Eskimo (1 3), the Japanese (15), the Oslo stud-
syndrome. despite the lack of clear criteria for its use in this ies (16) and from population-intervention studies and clinical
context. There are no data that support use ofthe bleeding time trials are highly suggestive and support the hypothesis that ,3
to predict bleeding: there is no evidence that the test changes fatty acids are contributing factors in the prevention of CHD
sufficiently in advance of serious bleeding to allow successful and in the control of blood pressure.
In considering dietary implications it is necessary to distinguish . The researchers urged that the appropriate government
among the various roles of w3 fatty acids: agencies officially recognize the vitally important differences
1) Omega-3 fatty acids are essential for normal growth and between co3 and c,6 polyunsaturated fatty acids. Estimates
development throughout the life cycle and they must be included of the average w3 nutrition consumption in the U.S. pre-
in the diet of pregnant women, premature infants, full-term in- sented by USDA scientists agreed with new nutrient mea-
fants. children, young adults, and elderly adults. As indicated surements reported from a NHLBI study, with both studies
in the previous section, the optimal intake of 18:3w3 was esti- indicating inadequate supplies ofw3 fatty acids in the typical
mated to be 800-1 100 mg/d and that of very-long-chain w3 American diet.
fatty acids to be 300-400 mg/d; the current amount in the US . New evidence with an extremely high level of statistical
population is 50 mg EPA and 80 mg DHA per capita per day, precision, from the National Heart, Lung and Blood Insti-
indicating that the present diet does not provide adequate tute study, suggests that the daily dietary intake of 0.5 to
amounts. I .0 grams of long chain w3 fatty acids per day reduces the
2) Increased intake of fish or fish oils may be necessary over risk ofcardiovascular death in middle aged American men
and above the amount determined for their essentiality, partic- by about 40%, and some new data suggests that w3 fatty
ularly in those who have a family history or other evidence of acids may also decrease cancer mortality.
susceptibility to CHD, hypertension, arthritis, psoriasis, and . The research reports make it increasingly evident that eating
cancer. o3 fatty acids can have beneficial effects on chronic inflam-
3) Omega-3 fatty acids are potentially valuable as adjuvants matory and cardiovascular diseases.
to treatment ofsome ofthese diseases.
Recently Canada published its 1990 nutrition recommenda-
It is interesting to consider the progress that has taken place
tions (203). As can be seen from Table 10, the Canadian nutrition

in dietary recommendations from 1985 to 1990. At the Con-
recommendations include separate recommendations for the two
ference on the Health Effects ofPolyunsaturated Fatty Acids in
classes of PUFAs. The amounts of w3 and u,6 fatty acids are
Seafoods in 1985, it was noted that in the United States the per
given in grams based on energy expressed as daily rates for the
capita consumption was 5.9 kg fish/y, which is equivalent to
various age groups from birth to 75+ y. For pregnancy additional
about one fish meal per week (24). A recommendation was made
w3 and w6 fatty acids are recommended in amounts that increase
to increase this amount to two to three fish meals per week. It
from the first to the second trimester. There is no increase be-
appears that the American public is responding because the cur-
tween the second and third trimester. Additional w3 and w6
rent per capita consumption has increased to 6.8 kg fish per
fatty acids are recommended during lactation.
year.
It was further recommended at the 1985 conference that total
fat intake should be 30% of total calories, with 10% being sat- Conclusions
urated fatty acids, 10% monounsaturated fatty acids, and 10%
PUFAs, the latter being equally divided between w6 and w3. Omega-3 fatty acids, LNA, EPA, and DHA, have been part
Therefore physicians should recommend the substitution of fish of the human diet throughout evolution. Modern agriculture
for meat so that fish is eaten at least twice per week. Alternatively, and aquaculture and the industrial revolution have led to changes
individuals who do not like fish and cannot get their w3 fatty in the production of both plants and animals and to marked
acids from their diet can get them from supplements. changes in the composition of the food supply of Western so-
An ideal supplement would contain high amounts of EPA cieties. Specifically, the amount of w6 fatty acids in the food
and DHA but little or no cholesterol or vitamins A and D. Vi- supply has increased and that of w3 fatty acids has decreased
tamin E should be added to prevent oxidation of these highly during human evolution from an estimated ratio of 1: 1 for w6:
unsaturated fatty acids. Products that conform to most of these w3 to 10: 1 or 20-25: 1 , based on various estimates.
requirements are produced from fish oils pressed or extracted Omega-3 fatty acids are found in human milk. Earlier animal
from the flesh of the fish. studies with rodents and nonhuman primates and recent studies
In the lay press there is confusion between fish-oil supplements with premature infants have shown that DHA is essential for
and cod-liver oil. Cod-liver oil extracted from the liver is rich the normal function of retina and brain. Additional studies in-
in vitamins A and D. Before the 1940s cod-liver oil was ingested dicate that w3 fatty acids are essential throughout the life cycle
mainly by children as a source of vitamins A and D. In the and many scientific groups have recommended establishing rec-
United Kingdom cod-liver oil is standardized by its vitamin ommended dietary allowance so that w3 fatty acids will be in-
content rather than its fish-oil content. In contrast, fish-oil sup- eluded in infant formulas and in enteral and parenteral solutions.
plements from the flesh offish contain only negligible amounts Furthermore, current data support recommendations for the
of vitamins A and D. general public. The 1990 Canadian nutrition recommendations

At the most recent conference, the Second International Con- already include specific amounts for w3 and w6 fatty acids (in
ference on the Health Effects ofOmega-3 Polyunsaturated Fatty g/d) for the various age groups, with additional amounts rec-
Acids in Seafoods(March 20-23, 1990), the following statement ommended during pregnancy and lactation. Thus, the great
was released: progress that has been made in nutrition research on the role of
w3 fatty acids in health and disease is already incorporated into
. Based upon clear evidence of an essential role for w3 fatty nutrition policy in Canada.
acids in human development and health, the scientists rec- Many investigators worldwide have examined the role of w3
ommended that all infant formula and diets for humans fatty acids in disease states. About 2000 studies involving animal
should include w3 fatty acids, and they expressed concern models, tissue cultures, clinical investigations, and randomized
that steps be taken to stop marketing enteral and parenteral double-blind clinical trials have been reported in the past 6 y in
formulas that fail to include any w3 fatty acids. the world literature. Such studies include normal subjects and
458 SIMOPOULOS
patients with atherosclerosis; CHD: hypertension; inflammatory 9. Sinclair H. Deficiency of essential fatty acids and atherosclerosis,
and autoimmune disorders such as arthritis, psoriasis, and ul- etcetera.Lancet l956;1:38l-3.
cerative colitis: and a number ofanimal models for research on 10. Bang HO, Dyerberg J. Plasma lipids and lipoproteins in Greenlandic
West-coast Eskimos. Acta Med Scand 1972;l92:85-94.
cancer.
1 1. Dyerberg I, Bang HO, Hjorne N. Fatty acid composition of the
The majority ofstudies have been earned out in patients with
plasma lipids in Greenland Eskimos. Am J Clin Nutr l975;28:
CVD. The role of w3 fatty acids, particularly EPA and DHA,
958-66.
has been investigated in terms of their hypolipidemic, anti- 12. Bang HO, Dyerberg J, Hjorne N. The composition of food con-
thrombotic, antiarrhythmic, antihypertensive, and anti-inflam- sumed by Greenland Eskimos. Acta Med Scand 1976;200:69-73.
matory aspects. Mechanisms include studies on eicosanoid pro- 13. Dyerberg J, Bang HO, Stofferson E. Eicosapentaenoic acid and
duction and metabolism, cytokine production and suppression, prevention of thrombosis and atherosclerosis. Lancet l978;2:
plasminogen activator production, and gene expression. Many 1 17-9.
of these studies indicate that w3 fatty acids appear to decrease 14. Dyerberg J, Bang HO. Haemostatic function and platelet poly-
or inhibit risk and precipitating factors in the development unsaturated fatty acids in Eskimos. Lancet 1979;2:433-5.
15. Hirai A, Terano T, Saito H, Tamura Y, Yoshida S. Clinical and
of CVD.
epidemiological studies ofeicosapentaenoic acid in Japan. In: Lands
Although an increase in consumption of w3 fatty acids alone
WEM, ed. Proceedings of the AOCS short course on polyunsatu-
clearly will not eradicate CVD, it is increasingly evident that
rated fatty acids and eicosanoids. Champaign, IL: American Oil
increasing the amount of w3 fatty acids in the Western diet by Chemists’ Society, I 987:9-24.
eating fish or supplementing the diet with fish oils may help in 16. Nordoy A, Goodnight S. Dietary lipids and thrombosis. Arterio-
the prevention of heart disease as well as in the prevention or sclerosis 1990; 10:149-63.
amelioration of other disease states. 17. Kromhout D, Bosschieter EB, Coulander C deL. The inverse re-
lation between fish consumption and 20-year mortality from con-

onary heart disease. N Engl J Med l985;312:1205-9.
Addendum 1 8. Shekelle RB, Missell L, Paul 0, Shryock AM, Stamler i. Fish con-
sumption and mortality from coronary heart disease. N EngI J
Since this paper was completed in November 1990, a paper Med 1985;3 13:820(letter).
was published in the December 1990 issue of The American 19. Norell SE, Ahlbom A, Feychting M, Pedersen NL. Fish consump-
Journal of Clinical Nutrition entitled “Erythrocyte fatty acids, tion and mortality from coronary heart disease. Br Med J l986;293:
plasma lipids, and cardiovascular disease in rural China” by 426.
Wenxun et al (2 1 1). In this paper the authors concluded that 20. Dolecek TA, Grandits G. Dietary polyunsaturated fatty acids and
within China neither plasma total cholesterol nor LDL choles- mortality in the Multiple Risk Factor Intervention Trial (MRFIT).
terol was associated with CVD. A strong inverse correlation be- In: Simopoulos AP, Kifer RR, Martin RE, Barlow SM, eds. Health
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Nutr Diet 199 l;66:205-l6.
However, erythrocyte oleate concentrations were not associated
21. Simonsen T, Vartun A, Lyngmo V, Nordoy A. Coronary heart
with plasma cholesterol but were strongly negatively associated
disease, serum lipids, platelets and dietary fish in two communities
with arachidonate concentrations, suggesting potential dimi- in northern Norway. Acts Med Scand 1987;222:237-45.
nution of CVD by oleate through reduced platelet aggregabil- 22. Hunter Di, Kazda I, Chockallngam A, Fodor JO. Fish consumption
ity. This study then implicates arachidonate in contributing and cardiovascular mortality in Canada: an interregional compar-
toCVD. ci ison. Am J Prey Med l988;4:5-6.
23. Burr ML, Fehily AM, Gilbert JF, et al. Effect ofchanges in fat, fish
I thank William Harris, Alexander Leaf, and Dwight Robinson for
and fibre intakes on death and myocardial reinfanction: diet and
their review and comments. reinfarction trial (DART). Lancet l989;2:757-6l.
24. Simopoulos AP, Kifer RR, Martin RE, eds. Health effects of poly-
unsaturated fatty acids in seafoods. Orlando, FL: Academic Press,
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A.P.. 1991. Omega-3 Fatty Acids in Health and Disease and in Growth and Development PDF

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Review Article

Omega-3 fatty acids in health and disease

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Date Title Type Institute

S Reproduced with permission from reference 29.

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Linoleate series Linolenat.e series

C18:2w6 Linoleic acid C18:3w3 Alpha-Iinolenic acid

Total Total Total Total

Bass, striped 2.3 0.5 0.7 0.8 Tr 0.2 0.6 80

Haddock 0.7 0. 1 0. 1 0.2 Tr 0. 1 0. 1 63

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Salmon, pink 3.4 0.6 0.9 1.4 Tr 0.4 0.6 -

Snapper, red 1.2 0.2 0.2 0.4 Tr Tr 0.2 -

Sole, European 1.2 0.3 0.4 0.2 Tr Tr 0. 1 50

Hwiler-Gcf hirer Agr/cu/tirc/ /#thistr#j/

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Trout (Salmo gairdneri and

Wild Cultured Wild Cultured Wild Cultured

Fat (g/lOO g) 5 ± 3 6 ± 1 21 ± 6 30 ± 2t 10 ± 0.1 16 ± 0.64

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PLANT METABOLISM MAMMALIAN METABOLISM

LinoIeic acid (w -6) foods Arachidonic acid Cl!3

Marine algae Leukotnienes 5

flt(tOfl \44 O24

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TABLE 7 most-important paper on atherosclerosis entitled “Atheroscle-

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for the prevention

ofCHD. Common genetic lipoprotein disorders associated with I M . Smooth musde

approved for the treatment of severe hypertriglyceridemia in \

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The effects of supplementing the diet with w3 fatty acids in Psoriasis

5HPE -:PE: THPDCHA t 4HPDCHA

5HETE 5HPE THDcHA ±

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LTB Lit4 -‘LTD -LTE

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Fatty acidt Human milk (n = 1 1) Portagen#{174}4 Enfamil Premature#{174}4 Similac Special §

8:0 (caprylic acid) 0.3 60 24.5 24.1

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a Reproduced with permission from reference 35.

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Age and sex Energy Thiamin Riboflavin Niacin w3 PUFAs w6 PUFAs

0-4 mo (M, F) 2.51 (600) 0.3 0.3 4 0.5 3

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S From reference 203.

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of vitamins A and D. general public. The 1990 Canadian nutrition recommendations

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